Methanol derivatives for treatment of retroviral infections especially HIV infections

ABSTRACT

The present invention relates to compounds of formula (I) which are imidazo[2,1-b]benzothiazole-3-methanol and imidazo[2,1-b]thiazole-5-methanol derivatives useful for inhibiting a retrovirus in a mammalian cell infected with said retrovirus, wherein R1 is -H or -CH3; wherein R2 is -H or -CH3; or wherein R1 and R2 taken together are (a) formula (II), or (b) formula (III).

This application is a 371 of PCT/US95/04444 filed Apr. 20, 1995, and aC-I-P of Ser. No. 08/236,417 filed Apr. 29, 1994 now abandoned.

FIELD OF THE INVENTION

The present invention relates to compounds useful for inhibiting aretrovirus in a human cell infected with said retrovirus. Moreparticularly, the present invention provides imidazo[2,1-b]thiazolederivatives as HIV-proteinase inhibitors.

BACKGROUND OF THE INVENTION

During the past decade, acquired immunodeficiency syndrome (AIDS) hasprogressed from having the status of a medical curiosity afflicting onlya small number of individuals to a problem of major proportions, bothmedically and economically. John Saunders and Richard Storer, “NewDevelopments in RT Inhibitors,” DN&P 5(3), April 1992, pages 153-169.WHO figures reveal that more than 360,000 cases of AIDS have beenreported worldwide, including nearly 175,000 cases in the U.S.A. Ofthese, approximately 100,000 worldwide (50,000 in the U.S.A.) werereported in the preceding 12-month period and WHO estimated over onemillion new infections during the first half of 1992. In the U.S.A., thenumber of seropositive individuals is thought to be approximately twomillion, and estimates suggest that 5-10 million people worldwide may beseropositive. Saunders and Storer, page 153.

Since the first description of the malady in the early part of thisdecade, acquired immunodeficiency disease syndrome (AIDS) and itsdevastating consequences have been subjects of continuous and intensecoverage in both the lay and scientific press. Indeed, an edition ofScientific American was entirely devoted to AIDS (Scientific American289, #4 (1988)), and the literature on the disease and the virus isalready so vast as to defy thorough citation.

On Mar. 20, 1987, the FDA approved the use of the compound, zidovudine(AZT), to treat AIDS patients with a recent initial episode ofpneumocystis carinii pneumonia, AIDS patients with conditions other thanpneumocystis carinii pneumonia or patients infected with the virus withan absolute CD4 lymphocyte count of less than 200/mm³ in the peripheralblood. AZT is a known inhibitor of viral reverse transcriptase, anenzyme necessary for human immunodeficiency virus replication. U.S. Pat.No. 4,724,232 claims a method of treating humans having acquiredimmunodeficiency syndrome utilizing 3′-azido-3′-deoxy-thymidine(azidothymidine, AZT).

Following the discovery of the anti-HIV activity of AZT, much effort hasbeen focused on a wide variety of other dideoxynucleoside analogues inthe search for superior agents. In the case of the 2′,3′-dideoxy series,ddC and ddI have shown potent activity against HIV in vitro and havebeen evaluated in clinical trials. Saunders and Storer, page 160. Thecompound ddC is currently being developed by Hoffman-La Roche Co. as apotential anti-AIDS drug. Its limiting toxicity in humans is peripheralneuropathy which is reversible at low doses. Raymond R. Schinazi, Jan R.Mead and Paul M. Feorino, “Insights Into HIV Chemotherapy,” AIDSResearch and Human Retroviruses, Vol. 8, Number 6, 1992, pages 963-990.It has been approved by the FDA for AIDS therapy in combination withAZT. The compound ddI has also been evaluated in clinical trials. Itslimiting toxicities are peripheral neuropathy and pancreatitis. It hasalso been shown to stimulate hepatic glycolysis leading to irreversibleliver damage. Schinazi, Mead and Feorino, page 966. It has recently beenapproved by the FDA for the treatment of HIV-1 infections in adults andpediatric patients who are intolerant to or whose health hassignificantly deteriorated while on AZT treatment. Schinazi, Mead andFeorino, page 966.

Among these approved drugs, AZT is currently the only drug that has beenshown to decrease the morality and frequency of opportunistic infectionsassociated with AIDS. Schinazi, Mead and Feorino, page 963.

Human immunodeficiency virus (HIV) has long been recognized as thecausative agent in AIDS, although a minority opinion to the contrary hasbeen expressed (e.g., P. Duesberg, Proc. Natl. Acad. Sci., USA,86:755-764 (1989)). Sequence analysis of the complete genomes fromseveral infective and non-infective HIV-isolates has shed considerablelight on the make-up of the virus and the types of molecules that areessential for its replication and maturation to an infective species.The HIV protease is essential for the processing of the viral gag andgag-pol polypeptides into mature virion proteins. L. Ratner, et al.,Nature, 313:277-284 (1985); L. H. Pearl and W. R. Taylor, Nature,329:351 (1987). HIV exhibits the same gag/pol/env organization seen inother retroviruses. L. Ratner, et al., above; S. Wain-Hobson, et al.,Cell, 40:9-17 (1985); R. Sanchez-Pescador, et al., Science, 227:484-492(1985); and M. A. Muesing, et al., Nature, 313: 450-458 (1985).

Reverse transcriptase (RT) is an enzyme unique to retroviruses thatcatalyzes the conversion of viral RNA into double stranded DNA. Blockageat any point during the transcription process, by AZT or any otheraberrant deoxynucleoside triphosphate incapable of elongation, shouldhave dramatic consequences relative to viral replication. Much work onthe RT target is in progress based, in large measure, upon the fact thatnucleosides like AZT are easily delivered to cells. However, theinefficiency of phosphorylation steps to the triphosphate, and the lackof specificity and consequent toxicity, constitute major drawbacks touse of AZT and similar nucleosides having a blocked, or missing,3′hydroxyl group.

The T4 cell receptor for HIV, the so-called CD4 molecule, has also beentargeted as an intervention point in AIDS therapy. R. A. Fisher, et al.,Nature, 331:76-78 (1988); R. E. Hussey, et al., Nature, 331:78-81(1988); and K. C. Deen, et al., Nature, 331:82-84 (1988). The exteriorportion of this transmembrane protein, a molecule of 371 amino acids(sCD4) has been expressed in Chinese hamster ovary (CHO) cells andGenentech (D. H. Smith, et al., Science, 238:1704-1707 (1987)) has had aproduct in clinical trials since the fall of 1987. CD4 has been shown tohave a narrow spectrum of activity against wild-type virus and so farhas failed to control HIV infection in humans. Schinazi, Mead andFeorino, page 963. The idea behind CD4 based therapy is that themolecules can neutralize HIV by interfering with viral attachment to T4,and other cells which express CD4 on their surfaces. A variant on thistheme is to attach cell toxins to CD4 for specific binding and deliveryto infected cells which display glycoprotein gp-120 on their surfaces.M. A. Till, et al., Science, 242:1166-1168 (1988); and V. K. Chaudhary,et al., Nature, 335:369-372 (1988).

Another therapeutic target in AIDS involves inhibition of the viralprotease (or proteinase) that is essential for processing HIV-fusionpolypeptide precursors. In HIV and several other retroviruses, theproteolytic maturation of the gag and gag/pol fusion polypeptides (aprocess indispensable for generation of infective viral particles) hasbeen shown to be mediated by a protease that is, itself, encoded by thepol region of the viral genome. Y. Yoshinaka, et al., Proc. Natl. Acad.Sci. USA, 82:1618-1622 (1985); Y. Yoshinaka, et al., J. Virol.,55:870-873 (1985); Y. Yoshinaka, et al., J. Virol., 57:826-832 (1986);and K. von der Helm, Proc. Natl. Acad. Sci., USA, 74:911-915 (1977).Inhibition of the protease has been shown to inhibit the processing ofthe HIV p55 in mammalian cell and HIV replication in T lymphocytes. T.J. McQuade, et al., Science, 247:454 (1990).

The protease (or proteinase), consisting of only 99 amino acids, isamong the smallest enzymes known, and its demonstrated homology toaspartyl proteases such as pepsin and renin (L. H. Pearl and W. R.Taylor, Nature, 329: 351-354 (1987); and I. Katoh, et al., Nature,329:654-656 (1987)), led to inferences regarding the three-dimensionalstructure and mechanism of the enzyme (L. H. Pearl and W. R. Taylor,above) that have since been borne out experimentally. Active HIVprotease has been expressed in bacteria (see, e.g., P. L. Darke, et al.,J. Biol. Chem., 264:2307-2312 (1989)) and chemically synthesized (J.Schneider and S. B. Kent, Cell, 54:363-368 (1988); and R. F. Nutt, etal., Proc. Natl. Acad. Sci., USA 85:7129-7133 (1988)). Site directedmutagenesis (P. L. Darke, et al., above); and N. E. Kohl, et al., Proc.Natl. Acad. Sci., USA, 85:4686-4690 (1988)) and pepstatin inhibition (P.L. Darke, et al., J. Biol. Chem., 264:2307-2312 (1989); S. Seelmeier, etal., Proc. Natl. Acad. Sci., USA, 85:6612-6616 (1988); C.-Z. Giam and I.Borsos, J. Biol. Chem., 263:14617-14720 (1988); and J. Hansen, et al.,EMBO J., 7:1785-1791 (1988)) have provided evidence for HIV protease'smechanistic function as an aspartyl protease. A study has demonstratedthat the protease cleaves at the sites expected in peptides modeledafter the regions actually cleaved by the enzyme in the gag and polprecursor proteins during viral maturation. P. L. Darke, et al.,Biochem. Biophys. Res. Communs., 156:297-303 (1988). X-raycrystallographic analysis of the HIV-protease (M. A. Navia, et al.,Nature, 337:615-620 (1989)) and a related retroviral enzyme from Roussarcoma virus (M. Miller, et al., Nature, 337:576-579 (1989)) reveal anactive site in the protease dimer that is identical to that seen inother aspartyl proteases, thus supporting the supposition (L. H. Pearland W. R. Taylor, above) that the HIV enzyme is active as a dimer. Seealso Joseph A. Martin, “Recent Advances in the Design of HIV ProteinaseInhibitors,” Antiviral Research, 17 (1992) 265-278.

To date, the scientific search for a fully effective and safe means ofinhibiting retroviruses in a human hosting such a virus, and therebyeffectively treating diseases caused by such a virus, such as acquiredimmunodeficiency syndrome (AIDS), continues.

INFORMATION DISCLOSURE

Published unexamined Japanese patent application 1-319488, Dec. 25,1989, from Nikken Chemicals Co. Ltd. describes the synthesis andantiulcer utility of tetrahydroimadazo[2,1-b]benzothiazole derivatives,including -3-methanol derivatives. Specifically disclosed are 3formyl-2-methyl-5,6,7,8-tetrahydro[2,1-b]benzothiazole and2-methyl-5,6,7,8-tetrahydro[2,1-b]benzothiazole-3-methanol.

Japanese patent 2-306918 (Dec. 20, 1990), from Nikken Chemicals Co. Ltd.describes imidazo[2,1-b]thiazole derivatives such as6-methyl-5-hydroxymethanol, 5-(1-hydroxybenzyl)-6-methyl,3,6-dimethyl-5-(1-hydroxybenzyl) derivatives.

Japanese patent 2-178289 (Jul. 11, 1990) describesimidazo[2,1-b]thiazoles for treatment of ulcers and for improvement ofcerebral function.

Japanese patent 2-306917 (Dec. 20, 1990) from Nikken Chemical Co. Ltd.describes imidazo[2,1-b]thiazoles derivatives such as 3,6-dimethylcompounds which have appended 5-carboxaldehyde, 5-hydroxymethyl and5-carboexthoxy substituents.

European patent 0 347 880 from Nikken Chemical Co. Ltd., describesimidazo[2,1-b]benzothiazoles derivatives such as:2-methylimidazo[2,1-b]benzothiazole-3-methanol hydrochloride;3-(1-hydroxyethyl)-2-methyl[2,1-b]benzothiazole;imidazo[2,1-b]benzothiazole-3-methanol;3-(60-hydroxybenzyl-2-methylimidazo[2,1-b]benzothiazole;7-methoxy-2-methylimidazo[2,1-b]benzothiazole-3-methanol; and7-fluoro-2-methylimidazo[2,1-b]benzothiazole-3-methanol.

European patent 0 463 212 from Nikko Chemical Co. Ltd. describesimidazo[2,1-6]thiazole-5-methanol compounds including3,6-dimethylimidazo[2,1-b]thiazole-5-methanol.

Costakis et al., Chem. Chron., 1978, 7, 171 (CA 91:20398t), describesthe synthesis of 2-chloro-3-(α-phenyl) and 2-chloro-3-(α-methyl)substituted phenyl imidazo[2,1-b]benzothiazole-3-methanol derivatives aswell as the corresponding 2,3-unsubstituted-6-chloro-5-(α-phenyl) and5-(α-substituted phenyl) imidazo [2,1-b]thiazole-5-methanol derivatives.

Abigmente et al., Il Famaco Ed. Sci., 1983, 38, 533, discloses a seriesof 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid and2-methylimidazo[2,1-b]benzothiazole-3-carboxylic acids, as well as theircorresponding esters.

Andreani et al., Eur. J. Med. Chem. Chim. Ther., 1986, 21 451, discloses2,3-unsubstituted and 2,3-dihydroimidazo[2,1-b]thiazole 5-carboxylicacids and their corresponding esters.

Compton et al., J. Chem. Soc. Perkin Trans., 1, 1992, 2029, disclose thesynthesis of methyl substituted (2,6-dimethyl, 2-methyl,3-methyl-6-phenyl and 6-phenyl) imidazo[2,1-b]thiazoles synthesized bydirect condensation with 2-aminothiazoles.

Robert et al., J. Heterocyclic Chem., 1979, 16, 1201, reportimidazo[2,1-b]thiazole-5-methane derivative, especially2,3-unsubstituted-methyl and -phenyl methanes.

Tisler et al. Heterocycles, 1986, 24, 279, disclose the synthesis of(imidazo[2,1-b]thiazol-5-yl)phenyl methanone derivatives.

The following references disclose variousimidazo[2,1-b]thiazole-5-carboxyaldehyde and aldehyde derivatives:

European patent 0 164 635 (CA 104:224897b) disclose hydrazonederivatives having diuretic and antihypertensive activities;

Yaoxue Zazhi, 1992, 44, 517 (CA 118:212949w) disclose 6-phenylderivatives having antiinflammatory activities;

J. Med. Chem., 1992, 35, 4634, disclose 2,3-dihydro and2,3-unsubstituted aminoguanidine derivatives having antitumor activity;

Pharma. Acta Helv., 1992, 67, 195 (CA 117:171315u) disclose hydrazonesulfonamide compounds having diuretic activity;

Andreani et al., Coll. Czech. Chem. Commun., 1991, 56, 2436) disclose3,6-dimethyl-5-carboxaldehyde derivatives having herbicidal activities;

O'Daley et al., J. Chem. Soc. Perkin Trans., 1, 1991, 855, disclose thesynthesis of 6-substituted and 3,6-disubstituted imidazothiazolesincluding the 3,6-dimethyl-5-carboxaldehyde;

Carloni et al., J. Heterocyclic Chem., 1989, 26, 525, discloseimidazo[2,1-b]thiazole-5-carboxaldehydes, notable 6-chloro and 6-phenylderivatives, having insecticidal activity;

Andreani et al., Eur. J. Med. Chem., 1988, 23, 385 and Il Farmaco, Ed.Sci., 1980, 35, 573, ibid, 1980, 35, 896, disclose5-carboxaldehyde-6-phenyl derivatives having antitumor activity; and

Acta. Pharma. Nord., 1992, 4, 93 (CA 111:208690t) discloses6-chloro-2,3-unsubstituted-5-carboxaldehyde hydrazone derivatives havingantihypertensive activity.

To the best of our knowledge, from our review, these references do notdisclose the use of these compounds as HIV protease inhibitors. They aredisclosed as being used or having activity as: antiulcer agents, agentsfor improving cerebral function, antiinflammatory, analgesic andantipyretic activity, cardiotonics, antihypertensives, antitumoractivity, diuretic activity, anticonvulsant agent, immunomodulators,immunoenhancers or immunosuppressants, neoplasm inhibitors, herbicidalactivity and insecticidal activity.

SUMMARY OF THE INVENTION

The present invention provides:

A compound of the formula I

wherein R₁ is —H or —CH₃;

wherein R₂ is —H or —CH₃; or

wherein R₁ and R₂ taken together are

a) the moiety of formula II, or

b) the moiety of formula III,

wherein p is 1 to 4 inclusive; or

wherein R₆ is

a) —H,

b) —CH₃,

c) —F, or

d) —OCH₃;

wherein R₃ is

a) —CH₂C₆H₅,

b) —CH₂CH₂C₆H₅,

c) —CH₂CH₂CH₂C₆H₅,

d) —CH₂CH₂CH₂CH₂C₆H₅,

e) —CH₂CH(CH₃)C₆H₅,

f) —CH₂CH₂C₆H₄X,

wherein X may occupy either the ortho, meta or para-positions and is

i) F,

ii) Cl,

iii) Br,

iv) OCH₂R₁,

v) N(CH₃)₂,

vi) NHSO₂CH₂R₁,

vii) SCH₃

viii) NHCOCH₂R₁, or

ix) NHSO₂C₆H₄X₁,

wherein X₁ is

a. H,

b. CH₃,

c. F, or

d. CN;

g) —CH═CH—C₆H₅, (cis or trans);

h) —C≡C—C₆H₅);

i) CH═CH—C₆H₃X₂

wherein X₂ is

a. F,

b. Cl,

c. OCH₃, or

d. —O—CH₂O;

wherein CH₂CH₂ is appended to the 1- or 2-positions; or

wherein

i) —CH₂CH₂— is appended to the 2- or 3-positions,

ii) X₃ is

a. O,

b. S,

c. NH, and

d. N—CH₃

iii) R₇ is appended to the 4- or 5-positions and is

a. CH₃, or

b. CH₃CH₂;

wherein R₄ is —H or —CH₃; and

wherein R₅ is —H or —CH₃;

provided that when R₁ is —CH₃ and R₂ is —H or —CH₃, R₃ and R₄ are not—H.

The compounds of the present invention are named according to the IUPACor CAS nomenclature system.

The compounds of formula I of the present invention inhibit retroviralproteinases and thus inhibit the replication of the virus. They areuseful for treating patients infected with human immunodeficiency virus(HIV) which results in acquired immunodeficiency syndrome (AIDS) andrelated diseases.

More particularly, the compounds of the present invention are useful asnovel human retroviral protease inhibitors. Therefore, the compoundsinhibit retroviral proteases and thus inhibit the replication of thevirus. They are useful for treating human patients infected with a humanretrovirus, such as human immunodeficiency virus (strains of HIV-1 orHIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) whichresults in acquired immunodeficiency syndrome (AIDS) and/or relateddiseases.

The capsid and replicative enzymes (i.e. protease, reversetranscriptase, integrase) of retroviruses are translated from the viralgag and pol genes as polyproteins that are further processed by theviral protease (PR) to the mature proteins found in the viral capsid andare necessary for viral functions and replication. If the PR is absentor nonfunctional, the virus cannot replicate. The retroviral PR, such asHIV-1 PR, has been found to be an aspartic protease with active sitecharacteristics similar to those exhibited by the more complex asparticprotease, renin.

The term human retrovirus (HRV) includes human immunodeficiency virustype I, human immunodeficiency virus type II, or strains thereof, aswell as human T cell leukemia virus 1 and 2 (HTLV-1 and HTLV-2) orstrains apparent to one skilled in the art, which belong to the same orrelated viral families and which create similar physiological effects inhumans as various human retroviruses.

Patients to be treated would be those individuals: 1) infected with oneor more strains of a human retrovirus as determined by the presence ofeither measurable viral antibody or antigen in the serum and 2) in thecase of HIV, having either an asymptomatic HIV infection or asymptomatic AIDS defining infection such as i) disseminatedhistoplasmosis, ii) isopsoriasis, iii) bronchial and pulmonarycandidiasis including pneumocystic pneumonia iv) non-Hodgkin's lymphomaor v) Kaposi's sarcoma and being less than sixty years old; or having anabsolute CD4+ lymphocyte count of less than 500/mm³ in the peripheralblood. Treatment would consist of maintaining an inhibitory level of thecompound used according to this invention in the patient at all timesand would continue until the occurrence of a second symptomatic AIDSdefining infection indicates alternate therapy is needed.

More specifically, an example of one such human retrovirus is the humanimmunodeficiency virus (HIV, also known as HTLV-III or LAV) which hasbeen recognized as the causative agent in human acquiredimmunodeficiency syndrome (AIDS), P. Duesberg, Proc. Natl. Acad. Sci.USA, 86:755 (1989). HIV contains a retro viral encoded protease, HIV-Iprotease, that cleaves the fusion polypeptides into the functionalproteins of the mature viral particle, E. P. Lillehoj, et al., J.Virology, 62:3053 (1988); C. Debuck et al., Proc. Natl. Acad. Sci.,84:8903 (1987). This enzyme, HIV-I protease, has been classified as anaspartyl protease and has a demonstrated homology to other aspartylproteases such as renin, L. H. Pearl, et al., Nature 329:351 (1987); I.Katoh, et al., Nature 329:654 (1987). Inhibition of HIV-I proteaseblocks the replication of HIV and thus is useful in the treatment ofhuman AIDS, E. D. Clerq, J. Med. Chem. 29:1561 (1986). Inhibitors ofHIV-I protease are useful in the treatment of HIV-infected individualswho are asymptomatic or symptomatic of AIDS.

Pepstatin A, a general inhibitor of aspartyl proteases, has beendisclosed as an inhibitor of HIV-I protease, S. Seelmeier, et al., Proc.Natl. Acad. Sci. USA, 85:6612 (1986). Other substrate derived inhibitorscontaining reduced bond isosteres or statine at the scissle positionhave also been disclosed, M. L. Moore, et al., Biochem. Biophys, Res.Commun. 159:420 (1989); S. Billich, et al., J. Biol. Chem. 263:17905(1988); Sandoz, D. E. 3812-576-A.

Thus, the compounds of the present invention are useful for treatingdiseases caused by retroviruses, such as human acquired immunodeficiencydisease syndrome (AIDS).

The compounds are also useful for treating non-human animals infectedwith a retrovirus, such as cats infected with feline leukemia virus.Other viruses that infect cats include, for example, feline infectiousperitonitis virus, calicivirus, rabies virus, feline immunodeficiencyvirus, feline parvovirus (panleukopenia virus), and feline chlamydia.Exact dosages, forms and modes of administration of the compounds of thepresent invention to non-human animals would be apparent to one ofordinary skill in the art, such as a veterinarian.

The compounds of formula I of the present invention are prepared,generally, as described in the Schemes below and, specifically, as inthe Charts, Preparations and Examples below, or are prepared by methodsanalogous thereto, which are readily known and available to one ofordinary skill in the art of organic synthesis.

The 2-aminothiazoles (Compounds 1a-1g) of Scheme I are eithercommercially available or, in the case of cycloalkyl derivatives, aresynthesized by condensing the corresponding halo ketone with thiourea asdescribed in the literature (U.S. Pat. No. 4,321,372; King, L. C.,Hlavacek, R. J., J. Am. Chem. Soc., 1950, 72, 3722). The2-aminothiazoles (1a-1g) were converted to amidines (2a-2g) by reactionwith dimethylformamide dimethyl acetal (R₁₃═H) or with dimethylacetamidedimethyl acetal (R₁₃═CH₃). These condensation reactions were performedin accordance with the work of Fajgeli et al., Heterocycles, 1986, 24,379.

The thiazolium salts (3, X═Cl⁻, Br⁻), obtained by reaction of theamidines (Compounds 2) with neat ethyl or methyl haloacetates (e.g.,BrCH₂CO₂CH₂CH₃), phenacylhalides (e.g., phenylacylbromide) orhaloacetone (ClCH₂COCH₃) readily found hydrates duringrecrystallization. Because the water of hydration is deleterious toyields in subsequent conversions, the salts were usually employed asprecipitated from the reations.

The imidazo[2,1-b]thiazole ring of Compounds 4 is conveniently generatedby cyclizations of the thiazolium salts with amine, alkali metalalkoxides or alkali metal hydride bases.1,8-Diaza-bicyclo[5,4,0]undec-7-ene (DBU) is a convenient basic amineuseful under the anhydrous conditions for the conversions. Thecorresponding α-alkyl (e.g., R₁₅═CH₃) α-substituted carbinols (6a-6g)are prepared by the reaction of the methyl ketone (Compound 4) withGrignard reagent. For example, additions of the Grignard reagents,derived from phenethyl bromide, to the ketones (4a-4g) produces thetarget imidazothiazole phenethyl carbinols (6a-g, R₁₄═CH₃,R₁₅═(CH₂)_(n)C₆H₄X (n=1-4, X═F, CL, Br, OCH₃).

Reduction of the ester of the imidazo[2,1-b]carboxylates (Compounds 4,R₁₄═OCH₃, OCH₂CH₃) with LiAlH₄ provide the intermediate primarycarbinols (Compounds 5, R₁₄═H) as an intermediate to the correspondingaldehydes (Compounds 7). The aldehydes are prepared by oxidation of theprimary alcohols (Compounds 5, R₁₄═H) with MnO₂ in refluxing toluene.The aldehydes provide an alternative intermediate for the addition ofphenyl and substituted Grignard reagents or phenyl lithium reagent inthe preparation of α-phenyl methanols. These aldehydes are readilycondensed with phenylethyl, benzyl, phenylpropyl, or phenylbutylmagnesium bromide derivatives to elaborate the corresponding side chainsof Compounds 8a-8g [R₁₆═(CH₂)_(n)C₆H₄X (n=1-4; X═H, F, CL, Br, OCH₃,N(CH₃)₂].

Scheme 2 illustrates the use of the methyl ketones 4a-4g for 2-carbonhomologation to the enones (Compounds 9). The aldehyde partners forcondensation with methyl ketones are commercially available in the casesof aryl and unsubstituted heterocyclic aldehydes. Substitutedheterocyclic aldehydes were available from literature preparations, forexample: J. Org. Chem., 1950, 15, 1177; J. Org. Chem., 1954, 19, 70; J.Org. Chem., 1984, 49, 4602; J. Org. Chem., 1985, 50, 2832; J. Org.Chem., 1987, 52, 104; J. Org. Chem., 1987, 52, 2315; Ziegler et al.,Tetrahedron Letters, 1981, 22, 4883; Tetrahedron, 1983, 39, 1893; Lund,T., Acta. Chem. Scand., See B., 1985 B39, 429; H. Kotsuki et al., Chem.Lett., 1983, 1007. Reduction of the enones with reagents known to favor1,4-reduction (sodium dithionite after Camps et al., Tetrahedron, 1986,42, 4603; Pd/C-limonene according to Von Holleben et al., Tetrahedron,1994, 50, 973; or Pd⁺²/potassium formate as described in Arcadi, A. etal., Syn. Lett., 1991, 27 or sodium hydrogen telluride after theprocedure of Tamashita et al, J. Org. Chem., 1994, 59, 3500) give thesaturated aryl- or heteroarylethyl ketones (11a-11-g). Hydroaluminationreaction (Koch et al., Tetrahedron Letters, 1994, 35, 1137) provide thesaturated alcohols (12) directly. Reduction reagents which favor1,2-reduction provide the allylic alcohols (10a-10g). The saturatedketones (11a-11g) are converted, respectively, with sodium borohydrideor Grignard reagents to the secondary methanols (12a-12g) or teriarymethanols (13a-13g).

The imidazo[2,1-b]benzothiazole derivatives are synthesized as in Scheme3. The 2-aminobenzothiazoles 14 are commercially available throughAldrich Chemical Company or other vendors. The amidines (15a-15c),benzothiazolium salts (16a-16e) and imidazobenzothiazole esters(17a-17e) follow from the chemistry of the methyl or cycloalkylderivatives in Scheme 1.

The other compounds of Scheme 3 are generated via the primary alcohols(18), aldehydes (19) as illustrated in Scheme 1 for the conversion ofthe carboxylic acid ester to the primary alcohols with lithium aluminumhydride and for conversion of the alcohols, in turn, to the aldehydeswith manganese oxide. The aldehydes (19) are reacted with the Grignardreagent derived from phenethyl bromide to produce the correspondingimidazobenzothiazole-3-phenylethyl carbinols (20).

As is apparent to those of ordinary skill in the art, the compounds ofthe present invention can occur in racemic or enantiomeric forms,depending on the configuration around the asymmetric carbon atoms. Allsuch forms are included within the scope of the present invention.

The present invention provides for compounds of formula I orphamacologically acceptable salts and/or hydrates thereof.Pharmacologically acceptable salts refers to those salts which would bereadily apparent to a manufacturing pharmaceutical chemist to beequivalent to the parent compound in properties such as formulation,stability, patient acceptance and bioavailability. Examples of suchsalts include the hydrohalide salts, such as the hydrochloride andhydroiodide salts, the sodium salt, the potassium salt, and the calciumsalt.

The compounds of the present invention are useful for treating patientsinfected with human immunodeficiency virus (HIV) which results inacquired immunodeficiency syndrome (AIDS) and related diseases. For thisindication, these compounds may be administered by oral, intranasal,transdermal, subcutaneous and parenteral (including intramuscular andintravenous) routes in doses of 0.1 mg to 100 mg/kg of body weight perday.

Those skilled in the art would know how to formulate the compounds ofthis invention into appropriate pharmaceutical dosage forms. Examples ofthe dosage forms include oral formulations, such as tablets or capsules,or parenteral formulations, such as sterile solutions.

When the compounds in this invention are administered orally, aneffective amount is from about 0.1 mg to 100 mg per kg of body weightper day. Either solid or fluid dosage forms can be prepared for oraladministration. Solid compositions are prepared by mixing the compoundsof this invention with conventional ingredients such as talc, magnesiumstearate, dicalcium phosphate, magnesium aluminum silicate, calciumsulfate, starch, lactose, acacia, methyl cellulose, or functionallysimilar pharmaceutical diluents and carriers. Capsules are prepared bymixing the compounds of this invention with an inert pharmaceuticaldiluent and placing the mixture into an appropriately sized hard gelatincapsule. Soft gelatin capsules are prepared by machine encapsulation ofa slurry of the compounds of this invention with an acceptable inert oilsuch as vegetable oil or light liquid petrolatum. Syrups are prepared bydissolving the compounds of this invention in an aqueous vehicle andadding sugar, aromatic flavoring agents and preservatives. Elixirs areprepared using a hydroalcoholic vehicle such as ethanol, suitablesweeteners such as sugar or saccharin and an aromatic flavoring agent.Suspensions are prepared with an aqueous vehicle and a suspending agentsuch as acacia, tragacanth, or methyl cellulose.

When the compounds of this invention are administered parenterally, theycan be given by injection of by intravenous infusion. An effectiveamount is from about 0.1 mg to 100 mg per kg of body weight per day.Parenteral solutions are prepared by dissolving the compounds of thisinvention in aqueous vehicle and filter sterilizing the solution beforeplacing in a suitable sealable vial or ampule. Parenteral suspensionsare prepared in substantially the same way except a sterile suspensionvehicle is used and the compounds of this invention are sterilized withethylene oxide or suitable gas before it is suspended in the vehicle.

The exact route of administration, dose, or frequency of administrationwould be readily determined by those skilled in the art and is dependanton the age, weight, general physical condition, or other clinicalsymptoms specific to the patient to be treated.

Patients to be treated would be those individuals: 1) infected with oneor more than one strain of a human immunodeficiency virus as determinedby the presence of either measurable viral antibody or antigen in theserum and 2) having either an asymptomatic HIV infection or asymptomatic AIDS defining infection such as i) disseminatedhistoplasmosis, ii) isoporiasis, iii) bronchial and pulmonarycandidiasis including pneumocystis pneumonia, iv) non-Hodgkin'slymphoma, or v) Kaposi's sarcoma and being less than sixty years old; orhaving an absolute CD4+ lymphocyte count of less than 500/mm³ in theperipheral blood. Treatment would consist of maintaining an inhibitorylevel of the compounds of this invention in the patient at all times andwould continue until the occurrence of a second symptomatic AIDSdefining infection indicates alternate therapy is needed.

The utility of representative compounds of the present invention hasbeen demonstrated in the biological tests described below:

The HIV protease screening assay is based on fluorescently labeledsubstrate which can be resolved from nonlabeled cleavage product usingspecial beads coated with streptavidin. The substrate is biotinylated atthe amino terminal arginine and fluorescently labeled with fluoresceinisothiocynate (FITC) at the carboxyl terminal lysine. This assay hasbeen employed to detect novel, nonpeptidic inhibitors of HIV-1 protease.Substrate (20 μl of 0.2 μM), sample (10 μl of desired concentration),and enzyme (10 μl of 0.1 μM) are added to a 96 well pandex plate. Theassay is run in 0.1 M sodium acetate buffer at pH 5.5 in the presence of1.0 M sodium chloride and 0.05% NP-40 with incubated in the dark for onehour at room temperature. Strepavidin coated polystyrene beads {40 μl of0.1% (w/v)} are added and the plate is incubated in the dark for anadditional half hour. The labeled cleavage product is separated from theunreacted substrate via filtration and is read on the Idexx screenmachine. The data are analyzed by appropriate computer algorithms toascertain percent inhibition values.

Determination of K_(i) values utilizes the same materials and equipmentemployed for percent inhibition studies. Two-fold serial dilutions aremade for a given inhibitor from 2, 3 or 4 starting concentrations with atotal of 24, 36 or 48 individual inhibitor concentrations. Thesedilutions are performed utilizing the BioMek robotics system. The assayconsists of 10 μL or 40 nM HIV-1 protease, 10 μL of the variousinhibitor concentrations, and 20 μL of 200 μM substrate (40 μL total).The reaction is allowed to proceed for 90 min at room temperature,terminated with 40 μL of avidin beads and processed (supra vide). Aninhibitor with a known K_(i) is run in parallel to verify the validityof the assay. The data is processed utilizing a computer programemploying a nonlinear least square analysis of the data to generate theK_(i) values.

The % inhibition values and, in some instances, IC₅₀ values or K_(i)values, of representative compounds of the present invention are listedin Table 1-Table 9 below.

The compounds of the present invention can be further evaluated in aCV-1 cellular assay described below, where it was demonstrated that theretrovirus-inhibiting effect was due to the inhibition of HIV-1protease:

Inhibition of p55 Processing in vVk-1 infected CV-1 Cells. CV-1 cellsare seeded at 2×10⁵ cells per well in 24-well Costar dishes and infected4 to 6 hours later with vVK-1 at 5 plaque-forming units (PFU) per cell.Each compound is dissolved in Dulbecco's Modified Eagles medium (DMEM)containing 2.5% fetal bovine serum and is added to duplicate wells atthe indicated final concentration 2 hours after virus addition. After 24hours, the culture medium is removed and the monolayer washed with 1 mLof phosphate buffered saline (PBS), and the cells lysed by the additionof 0.1 mL of loading buffer (62.5 mM Tris (hydroxymethyl) aminomethane(Tris), pH 6.8, 2.3% sodium dodecyl sulfate (SDS), 5% β-mercaptoethanol,and 10% glycerol). The cell lysates are collected individually, placedin boiling water for 3 minutes, and then 0.025 mL of each sample issubjected to electrophoresis on 12% SDS-polyacrylamide gels. Theproteins are electroblotted onto nitrocellulose and analyzed by proteinimmunoblotting. The primary antibodies are sheep antibody to p24(International Enzyme, Inc., Fallbrook, Calif.) and the secondaryantibody is alkaline-phosphatase-conjugated rabbit antibody to sheepimmunoglobulin G (Kirkegaard & Perry Laboratories, Gaithersburg, Md.).The levels of immunoreactive proteins are quantified by densitometry(Bio-Rad, Model 260) with the accompanying 1-D Analyst Software.Inhibition refers to the mean percent decrease in p24 levels determinedfrom the duplicate drug-treated samples compared to the nondrug-treatedcontrols. In general, the percent inhibition did not vary more than 10%in the duplicates. The inhibition of p24 levels by treatment of cultureswith 1 μM of peptide 1-Noa-His-Cha PSI [CHOHCHOH] Val-Ile-Amp (alsoknown asN-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-α-[[(1-naphthalenyloxy)acetyl]amino]-,[1S-[1R*(R*),2S*,3S*,4S*(1R*,2R*))]]-1-H-imidazole-4-propanamide) (whichwas disclosed in International Publication Number WO 87/05302, publishedSep. 11, 1987) was also determined in each experiment.

Several compounds of the present invention, such as2,3-dimethyl-60-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol weretested in known human cell lines, such as human T-cell lines, e.g., H9,which were infected with HIV-1_(IIIB). The compounds were found toinhibit retroviral replication. The H9 cell line was originally derivedfrom the peripheral blood of a human lymphoma patient and extensivelycloned so that the cells were highly susceptible to HIV infection.Virus-free H9 cells were maintained in a humidified 5% CO₂ atmosphere at37° C. in RPMI Complete (RC) medium, which was composed of RPMI 1640supplemented with 10% heat-inactivated fetal calf serum (FCS), 10 mMHepes, 2 mM L-glutamine, 100 μg/ml streptomycin, and 100 U/mlpenicillin. H9 cultures were split 1:5 twice weekly for a maximum 12-15times. New lots of cells were obtained from cryopreserved samples frozenin liquid nitrogen vapor and maintained in RPMI 1640 containing 20% FCS,10 mM Hepes, 2 mM L-glutamine, 100 U/ml penicillin, 100 μg/mlstreptomycin, and 7.5% DMSO.

HIV_(IIIb)'s ability to replicate efficiently in human T lymphoblastoidcell lines made this strain of HIV the logical choice for proteaseinhibitor screen. Viral stocks were created by acutely infecting 2×10⁶H9 cells contained in 1 ml RC medium at a multiplicity of infection of0.1. The infected cells were transferred to 50 ml of RC, and split 1:3biweekly, with cell viability ranging from 65-80%. Fourteen days afterthe infection was established, culture supernatant was removed andfrozen at −80° C. with no preservatives added. The supernatant,containing a high titer of HIV_(IIIb) particles, was thawed, centrifugedat 200×g to remove cell debris, then distributed in 0.5 ml aliquots tocryogenic vials. The titer, measured at the 50% Tissue CultureInfectious Dose (TCID₅₀), was determined by the Reed-Muench method ofstatistical analysis to determine the 50% infectivity endpoint.

The standard acute infectivity assay for the evaluation of theinhibitors of HIV protease was performed in 96 well microplates. H9cells were washed and resuspended to a concentration of 2×10⁶ cells/mlin RC Medium. 25 μl of H9 cells were distributed to the appropriatewells of a microtiter plate so that the final concentration of cells was5×10⁴/well. To each well except negative controls, 25 μl of HIV_(IIIb)containing approximately 50 TCID₅₀'s was added, achieving a multiplicityof infection of 0.001. Finally, 25 μl of 3× drug was added to the wells.To the control well, 25 μl of either RC medium or RC+DMSO was added. Theamount of DMSO utilized in the control wells was equivalent to the DMSOcontent of the test drugs. The microplates were incubated in ahumidified 5% CO₂ atmosphere for 2 h at 37° C. At the end of theincubation period, an additional 175 μl of 1× drug, RC medium, orRC+DMSO was added to each test well, and the plates incubated for 7 daysat 37° C. in 5% CO₂. Each drug concentration was tested in triplicate.Each compound was originally tested at 100, 10 and 1 nM to assessanti-HIV activity, and active compounds were retested using serial 0.5log₁₀ dilutions beginning at concentrations of 100 nM or below. Afterfour days of incubation, 125 μl of the cell culture supernatant in eachwell was removed without disturbing the cells and replaced with 125 μlof fresh RC Medium, RC+DMSO, or RC+1× drug. At the end of the 7 dayincubation period, 100 μl of supernatant was removed from each test welland live virus inactivated by the addition of lysis buffer containing 5%Triton X-100. The amount of HIV p24 core antigen was quantified with anELISA procedure by following the manufacturers directions (CoulterDiagnostics). The IC₅₀ (Inhibitory Concentration₅₀), the amount of drugnecessary to reduce the concentration of p24 in drug-containing culturesby 50% when compared with drug-free controls, was calculated bycomparing the concentration of p24 antigen from the drug test wells tothe p24 levels found in the drug-free control growth wells.

An in vitro assay capable of assessing the activity of antiviralcompounds against HIV_(IIIb) in H9 cells was developed. The assaycompares the ability of the human immunodeficiency virus to replicate inthe presence or absence of drug. Replication is assessed by the abilityof the virus to produce p24 core antigen, as determined by an ELISAtechnique. Production of p24 in the presence of drug is compared withdrug-free controls, and the Inhibitory Concentration₅₀ (IC₅₀) calculatedby linear regression.

The following compounds of the present invention are preferred:

2,3-Dimethyl-α-(2-phenylethynyl)imidazo-[2,1-b]thiazole-5l-methanol,

2,3-Dimethyl-α-(2-phenylmethyl)imidazo-[2,1-b]thiazole-5-methanol,

2,3-Dimethyl-α-(3-phenylpropyl)imidazo-[2,1-b]thiazole-5-methanol,

2,3-Dimethyl-α-Di(2-phenylethyl)imidazo-[2,1-b]thiazole-5-methanol,

α,3-Dimethyl-α-(E-2-phenyl-E-ethenyl)imidazo[2,1-b]thiazole-5-methanol,

3-Methyl-α-(2-phenylpropyl)imidazo[2,1-b]thiazole-5-methanol,

α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,

3-Methyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,

3-Methyl-α-(4-bromophenylethyl)imidazo[2,1-b]thiazole-5-methanol,

3-Methyl-α-(4-phenylbutyl)imidazo-[2,1-b]thiazole-5-methanol,

2,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,

2,3-Dimethyl-α-(2-phenylethenyl)imidazo[2,1-b]thiazole-5-methanol,

6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol,

5,6,7,8-Tetrahydro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,

6,7,8,9-Tetrahydro-α-(2-phenylethyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol,

6,7,8,9-Tetrahydro-α-(4-phenylbutyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol,

5,6,7,8,9,10-Hexahydro-α-(2-phenylethyl)cyclooct[d]imidazo-[2,1-b]thiazole-3-methanol,

α-(2-phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol,

7-Methyl-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,

7-Fluoro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,

7-Methoxy-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,

α-[2-(3-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-imidazo[2,1-b]thiazole-3-methanol

α-[2-(3-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,

α-[2-(4-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,

α-[2-(4-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,

α-[2-(3-Bromophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-2,1-b]thiazol-3-methanol,

α-[2-(3-Chlorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,

α-[2-(3,5-Difluorophenyl)ethyl]-1-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazothiazol-3-methanol,

α-[2-(4-dimethylaminophenyl)ethyl-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-[2,1-b]thiazol-3-methanol,

α-[2-(4-Dimethylaminophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-methanol,

N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxypropyl]phenyl-4-methylbenzenesulfonamide,

(E)-N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-1-propenyl]phenyl-4-methylbenzenesulfonamide,

N-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-propyl]phenyl-4-methylbenzenesulfonamide,

α-[2-(2,3-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-thiazol-3-methanol,

α-[2-(4-methoxyphenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1b]thiazol-3-methanol,

α-[2-(4-methoxyphenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol,

α-[2-(2-Naphthalenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,

α-[2-(2-Furanyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,

α-[2-(2-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,

α-[2-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,

α-[2-(2-Furanyl)ethenyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol,

α-[2-(2-Furanyl)ethyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol, and

1-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-phenyl-1,3-propanediol.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the Preparations and Examples below and throughout this document:

°C. is degrees Centigrade

M is molar (concentration).

N is normal (concentration).

mL is milliliter.

mg is milligram.

mmHg is millimeter of mercury.

¹H-NMR is proton nuclear magnetic resonance spectrum.

¹³C-NMR is carbon nuclear magnetic resonance spectrum.

δ is chemical shift (parts per million) relative to TMS.

CDCl₃ is deuterio-chloroform.

CD₃OD is deuterio-methanol.

DMSO is deuterio dimethylsulfoxide.

FAB MS is fast-atom-bombardment mass spectroscopy.

EI MS is electron impact mass spectroscopy.

HRMS is high-resolution mass spectroscopy.

Anal. is analytical data.

Pd/C is palladium on charcoal.

THF is tetrahydrofuran.

HOBT is 1-hydroxybenzotriazole hydrate.

R_(f) is chromatographic movement relative to solvent front.

cm⁻¹ is reciprocal centimeters.

TFA is trifluoroacetic acid.

MP is melting point.

TMS is tetramethyl silane.

The following Preparations and Examples, which illustrate thepreparation of certain presently preferred compounds according to theinvention, are for illustrative purposes only and are not to beconstrued as limiting the invention.

PREPARATION 1 N′-(4,5-Dimethyl-2-thiazolyl)-N,N-dimethyl-methanimidamide(Formula A-2) Refer to Chart A.

A suspension of 2-amino-4,5-dimethylthiazole hydrochloride (4.92 g, 30mmol) (Formula A-1) in toluene (60 mL) was treated with triethylamine(4.5 mL, 35 mmol) and vigorously stirred for 30 minutes. The mixture wastreated with dimethylformamide dimethyl acetal (7.3 mL, 60 mmol) andheated at reflux temperature for 2 hours. The solution was cooled,diluted with ethyl acetate, washed with saline, dried and evaporated.The residue was crystallized from hexane to provide pureN′-(4,5-Dimethyl-2-thiazolyl)-N,N-dimethyl-methanimidamide (Formula A-2)(4.31 g, 77%), m.p. 47-58°.

Anal. Calc'd for C₈H₁₃N₃S: C, 52.42; H, 7.14; N, 22.92; S, 17.49. Found:C, 52.31; H, 7.27; N, 22.87; S, 17.65. MS m/z 183 (M⁺), 168, 150, 141,113, 98, 86, and 71. NMR (CDCl₃) 2.22 (s, 3, CH₃), 2.26 (s, 3, CH₃),3.10 (s, 6, CH₃), 8.10 (s, 1, CH).

PREPARATION 24,5-Dimethyl-2[[(dimethylamino)methylene]amino-3-(2-ethoxy-2-oxoethyl)-thiazoliumbromide (Formula A-3) Refer to Chart A.

A solution of N′-(4,5-Dimethyl-2-thiazolyl)-N,N-dimethyl-methanimidamide(Formula A-2) (13.74 g, 75 mmol) in ethyl bromoacetate (25 mL)solidified within 45 minutes. Additional reagent (15 mL) and toluene (30mL) were added to maintain fluididy. The mixture was reacted at 25° for48 hours, diluted with ethyl acetate (200 mL) and the precipitated4,5-Dimethyl-2[[(dimethylamino)methylene]amino-3-(2-ethoxy-2-oxoethyl)-thiazoliumbromide (Formula A-3) (23.49 g, 89%) was filtered. An aliquot wascrystallized from acetonitrile to provide an analytical sample, m.p.178-180°.

Anal. Calc'd for C₁₂H₂₀BrN₃O₂S: C, 41.15; H, 5.76; Br, 22.81; N, 12.00;S, 9.15. Found: C, 41.10; H, 5.67; Br, 22.91; N, 11.99; S, 9.19. MS m/z(FAB) 621, 619 (2M⁺-Br), 270 (M⁺+H-Br). IR (mull) 1743, 1646, 1628,1522, 1489, 1434, 1425, 1411, 1397, and 1218 cm⁻¹.

PREPARATION 3

2,3-DImethylimidazo[2,1-b]thiazole-5-carboxylic acid ethyl ester(Formula A-4) Refer to Chart A.

A suspension of4,5-Dimethyl-2-[[(dimethylamino)methylene]amino-3-(2-ethoxy-2-oxoethyl)-thiazoliumbromide (Formula A-3) (10.42 g, 29.8 mmol) in DMF (40 mL) was treatedwith DBU (7.0 mL, 7.17 g, 47.2 mmol). Dissolution of4,5-Dimethyl-2[[(dimethylamino)methylene]amino-3-(2-ethoxy-2-oxoethyl)-thiazoliumbromide (Formula A-3) occurred immediately and the solution was reactedat ambient temperature for 24 hours. The solution was diluted with icewater and precipitated 2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxylicacid ethyl ester (Formula A-4) (4.36 g, 65%) was filtered. Theprecipitate contained polar by-products which were removed by filtrationof the crude product through silica gel (200 g) eluting with 4:1hexane:ethyl acetate. The eluted product (2.28 g) was crystallized fromethyl acetate-hexane solution to provide pure2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxylic acid ethyl ester(Formula A-4) (1.77 g), m.p. 60-61°.

Anal. Calc'd for C₁₀H₁₂N₂O₂S: C, 53.55; H, 5.39; N, 12.49; S, 14.29.Found: C, 53.43, H, 5.45; N, 12.00; S, 14.10.

MS m/z 224 (M⁺), 196, 195, 179, 178, 167, 152, 150, 139, 137 and 110.

IR 1721, 1506, 1436, 1395, 1354, 1308, 1216, 1170, 1135, and 1063 CM⁻¹.

NMR (CDCl₃) δ 1.38 (t, J=7 Hz, 3, CH₃), 2.34 (s, 3, CH₃), 2.63 (s, 3,CH₃), 4.31 (q, J=7 Hz, 2, CH₂), 7.93 (s, 1, CH).

PREPARATION 4

2,3-Dimethylimidazo[2,1-b]thiazole-5-methanol (Formula A-5) Refer toChart A.

A solution of 2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxylic acid ethylester (Formula A-4) (1.68 g) in THF (50 mL) at 0° was treated withLiAlH₄ (0.38 g) and reacted at 25° for 1.5 hours. Excess reagent wasquenched by sequential addition of water and 15% sodium hydroxide. Theresulting mixture was diluted with THF (100 mL), filtered, and thefiltrate was evaporated to a residue of crude2,3-Dimethylimidazo[2,1-b]thiazole-5-methanol (Formula A-5) (1.04 g).Crystallization from isopropanol solution gave pure2,3-Dimethylimidazo[2,1-b]thiazole-5-methanol (Formula A-5), m.p.166-167°.

Anal. Calc'd for C₈H₁₀N₂OS: C, 52.72; H, 5.53; N, 15.37; S, 17.59.Found: C, 52.84; H, 5.54; N, 15.40; S, 17.50.

MS m/z 182 (M⁺), 165, 153, 129, 128, and 113.

IR (mull) 3188, 3115, 1654, 1335, 1324, 1310, and 1019 cm⁻¹.

NMR (CDCl₃) δ 2.32 (s, 3, CH₃), 2.54 (s, 3, CH₃), 4.78 (s, 2, CH₂), 7.07(s, 1, CH).

PREPARATION 5

2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6) Referto Chart A.

A solution of 2,3-Dimethylimidazo[2,1-b]thiazole-5-methanol (FormulaA-5) (4.38 g) in DMF (30 mL) was diluted with toluene (400 mL), treatedwith MnO₂ (8.8 g) and azetropically distilled during 2 hours. The cooledmixture was diluted with ethyl acetate, filtered, and the filtrate wasevaporated. The residue was diluted with water and precipitated2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6) (4.12g) was filtered. Crystallization from ethyl acetate hexane provided pure2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6), m.p.119-120°.

Anal. Calc'd for C₈H₈N₂OS: C, 53.33; H, 4.48; N, 15.55; S, 17.79. Found:C, 53.44; H, 4.47; N, 15.64; S, 17.70.

MS m/z 180 (M⁺), 179, 165, 151, 147, and 110.

IR (mull) 1676, 1671, 1507, 1448, 1389, 1345, 1327, 1301, 1268, 1165 and1161 cm⁻¹.

NMR (CDCl₃) 2.36 (s, 3, CH₃), 2.69 (s, 3, CH₃), 7.97 (s, 1, CH), 9.57(s, 1, CH).

EXAMPLE 1

2,3-Dimethyl-α-(2-phenylethynyl)imidazo-[2,1-b]thiazole-5-methanol(Formula A-7) Refer to Chart A.

Phenylacetylene (0.73 g) in THF (10 mL) at −65° was treated with 1.6 Mn-butyllithium in hexane (0.44 mL). The solution was reacted for 30minutes then treated with a solution of2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6) (0.64g) in THF (10 mL). The solution was reacted at −65° for 1.5 hours thenat 25° for 6 hours. Incomplete conversion of2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6)persisted after 24 hours and the reaction suspension was poured into icewater and products were extracted into ethyl acetate. Drying andevaporation of solvent gave an oil which deposited pure crude2,3-Dimethyl-α-(2-phenylethynyl)imidazo-[2,1-b]thiazole-5-methanol(Formula A-7) (0.16 g) from hexane. Crystallization from ethanol gavepure 2,3-Dimethyl-α-(2-phenylethynyl)imidazo-[2,1-b]thiazole-5-methanol(Formula A-7).

MS (m/z) 282 (M⁺), 265, 253, 239, 205, 180, 179, 152, 139, and 129.

NMR (DMSO) δ 2.32 (s, 3, CH₃), 2.65 (s, 3, CH₃), 6.05 (d, 1, OH), 6.48(d, 1, CH), 7.32 (s, 1, CH), 7.40-7.60 (m, 5, ArH).

EXAMPLE 2

2,3-Dimethyl-α-(2-phenylmethyl)imidazo-[2,1-b]thiazole-5-methanol(Formula A-8) Refer to Chart A.

Magnesium (0.29 g) in ether (20 mL) was treated with benzyl bromide(0.179 mL) and reacted at ambient temperature for 1.25 hours. Solid2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6) (0.54g) was added and the thick suspension reacted for 24 hours. The mixturewas poured into cold 5% ammonium chloride solution and the mixture wasextracted with ethyl acetate. Evaparation of the extract gave asemi-solid residue (1.22 g) of crude2,3-Dimethyl-α-(2-phenylmethyl)imidazo-[2,1-b]thiazole-5-methanol(Formula A-8). Trituration of the residue with cold ether gave pure2,3,-Dimethyl-α-(2-phenylmethyl)imidazo-[2,1-b]thiazole-5-methanol(Formula A-8) (0.59 g). Crystallization of the triturated product fromacetonitrile provided an analytical sample, m.p. 170-172°.

Anal. Calc'd for C₁₅H₁₆N₂OS: C, 66.15; H, 5.92; N, 10.29; S, 11.77.Found: C, 66.22; H, 5.99; N, 10.49; S, 11.66.

MS m/z 272 (M⁺), 255, 253, 183, 182, 181, 153, 129, 115, and 99.

IR (mull) 3129, 3111, 3086, 3063, 3057, 1628, 1602, 1548, 1496, 1322,1309, 1296, 1143, and 1055 cm⁻¹.

NMR (CDCl₃) 2.29 (s, 3, CH₃), 2.51 (s, 3, CH₃), 3.22 (q, 1, CH₂), 3.36(q, 1, CH₂), 5.15 (m, 1, CH), 7.18 (s, 1, CH), 7.31 (m, 5, ArH).

EXAMPLE 3

2,3-Dimethyl-α-(3-phenylpropyl)imidazo-[2,1-b]thiazole-5-methanol(Formula A-9) Refer to Chart A.

Magnesium (0.29 g) in ether was treated with 1-bromo-3-phenylpropane(2.38 g) and reacted for 5 hours. Solid2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6) (0.72g) was added and the viscous mixture was reacted for 1.5 hours. Thethick suspension was diluted with ether and poured into cold 5% ammoniumchloride solution. The mixture was extracted with ethyl acetate, theextract was dried and evaporated to a semi-crystalline residue (1.6 g).The residue, containing unreacted2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6), wastriturated with ether, filtered and the filter cake (0.50 g) wasrecrystallized from acetonitrile to yield pure2,3-Dimethyl-α-(3-phenylpropyl)imidazo-[2,1-b]thiazole-5-methanol(Formula A-9) (0.38 g), m.p. 167-169°.

Anal. Calc'd for C₁₇H₂₀N₂OS: C, 67.97; H, 6.71; N, 9.32; S, 10.67.Found: C, 67.86; H, 6.76; N, 9.25; S, 10.53.

MS m/z 300 (M⁺), 283, 273, 255, 241, 181, 153, and 91

IR (mull) 3262, 3116, 3080, 3062, 3047, 3023, 1602, 1493, 1391, 1325,1316, 1288, 1270, 1241, 1147, 1139, and 1079 cm⁻¹.

NMR (CDCl₃) 1.67-2.10 (m, 4, CH₂), 2.29 (s, 3, CH₃), 2.50 (s, 3, CH₃)2.70 (m, 2, CH₂), 4.87 (m, 1, CH), 6.97 (s, 1, CH), 7.1-7.35 (m, 5,ArH).

EXAMPLE 4

2,3-Dimethyl-α-Di(2-phenylethyl)imidazo-[2,1-b]thiazole-5-methanol(Formula A-10) Refer to Chart A.

Magnesium (0.313 g) in ether (25 mL) was treated with2-(bromoethyl)benzene (2.37 g) and reacted with 2.25 hours. Solid2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxylic acid ethyl ester(Formula A-4) (0.29 g) was added and the thick suspension was vigorouslystirred for 4.5 hours. The mixture was quenched into 5% ammoniumchloride solution and product was extracted into ethyl acetate. Dryingand evaporation of solvent gave a semi-crystalline residue (0.88 g). Theresidue was triturated with ether, filtered, and the filter cake (0.34g) was crystallized from methylene chloride-isopropanol solution toprovide pure2,3-Dimethyl-α-Di(2-phenylethyl)imidazo-[2,1-b]thiazole-5-methanol(Formula A-10) (0.25 g), m.p. 145-146°.

Anal. Calc'd for C₂₄H₂₆N₂OS: C, 73.81; H, 6.71; N, 7.17; S, 8.21. Found:C, 73.76; H, 6.75; N, 7.08; S, 8.26.

MS m/z 390 (M⁺), 372, 285, 267, 241, 194, 193, 179, 165, 153, and 91.

IR (mull) 3145, 3134, 3084, 3064, 3057, 3037, 3025, 1601, 1532, 1494,1310, 1289, 1177, 1166 and 1057 cm⁻¹.

NMR (CDCl₃) δ 2.25-2.43 (m, 7, CH₃, CH₂), 2.50-2.62 (m, 3, CH₂, OH),2.65 (s, 1, CH₃), 2.7-2.9 (m, 2, CH₂), 7.09 (s, 1, CH), 7.12-7.32 (m,10, ArH).

PREPARATION 6

2-Phenyl-E-ethenyl)-3-methylimidazo[2,1-b]thiazol-5-yl methanone(Formula B-2) Refer to Chart B.

A solution of 1-(3-methylimidazo[2,1-b]thiazol-5-yl)ethanone(synthesized by the generic procedure described above were R₁₄=CH₃modified according to Fajgeli et al., Heterocycles, 1986, 24, 379 andCopar et al., J. Heterocyclic Chem., 1993, 30, 1577. (7.21 g) in THF(100 mL) was treated with benzaldehyde (6.99 g) and sodium methoxide(1.08 g) and reacted for 3 hours. The solution was diluted with icewater and the precipitated2-Phenyl-E-ethenyl)-3-methylimidazo[2,1-b]thiazol-5-yl methanone(Formula B-2) (10.8 g) was filtered. An aliquot was recrystallized fromisopropanol as an analytical sample, m.p. 150-152°.

Anal. Calc'd for C₁₅H₁₂N₂OS; C, 67.14; H, 4.51; N, 10.44; S, 11.95.Found: C, 66.90; H, 4.60; N, 10.40; S, 11.89.

MS m/z 268 (M⁺), 267, 240, 239, 191, 177, 165, 138 and 103.

IR (mull) 3093, 1647, 1591, 1574, 1447, 1421, 1363, 1300, 1193, and 1034cm⁻¹.

NMR (CDCl₃) δ 2.80 (s, 3, CH₃), 6.55 (s, 1, CH), 7.30 (d, J=16 Hz, 1,CH), 7.42 (m, 3, ArH), 7.62 (m, 2, ARH), 7.78 (d, J=15 Hz, 1, CH), 8.15(s, 1, CH).

EXAMPLE 5

α,3-Dimethyl-α-(E-2-phenyl-E-ethenyl)imidazo[2,1-b]thiazole-5-methanol(Formula B-4) and 2-phenylpropyl-3-methylimidazo[2,1-b]thiazol-5-ylmethanone (Formula B-3) Refer to Chart B.

A suspension 2-Phenyl-E-ethenyl)-3-methylimidazo[2,1-b]thiazole-5-ylmethanone (Formula B-2) (1.07 g) in THF (26 mL) at −78° was treated with3M ethereal methyl magnesium bromide (1.47 mL) and the mixture wasreacted at −15 to −20° for 18 hours. Additional reagent (0.30 mL) wasadded and reacted at 25° for 1.5 hours. The reaction mixture was pouredinto cold 5% NH₄Cl solution and products were extracted into ethylacetate. The residue from drying and evaporation of solvent depositedα,3-Dimethyl-α-(E-2-phenyl-E-ethenyl)imidazo[2,1-b]thiazole-5-methanol(Formula B-4) (0.22 g) from ether solution. The filtrate residue (1.0 g)was fractionated on silica gel (100 g); 85:15 hexane:ethyl acetateeluted 2-phenylpropyl-3-methylimidazo[2,1-b]thiazol-5-yl methanone(Formula B-3) (0.44 mg), 1:1 ethyl acetate:hexane elutedα,3-Dimethyl-α-(E-2-phenyl-E-ethenyl)imidazo[2,1-b]thiazole-5-methanol(Formula B-4) (0.41 g), m.p. 145-147° after ethyl acetate hexanecrystallization.

Formula B

Anal. Calc'd for C₁₆H₁₆N₂OS: C, 67.58; H, 5.67; N, 9.85; S, 11.28,Found: C, 67.21; H, 5.68; N, 9.79; S, 11.10.

MS m/z 284 (M⁺), 241, 152, 151, 139, 138 and 131.

IR (mull) 3340, 3245, 1448, 1367, 1271, 1178, 1159, 1117 and 1093 cm⁻¹.

NMR (CDCl₃) 1.91 (s, 3, CH₃), 2.3 (b, 1, OH), 2.57 (s, 3, CH₃), 6.24 (d,J=Hz, 1, CH), 6.30 (s, 1, CH), 6.54 (d, J=16 Hz, 1, CH), 7.32 (m, 5, CH,ArH).

Formula B-3

NMR (CDCl₃) δ 1.34 (d, J=7 Hz, 3, CH₃), 2.67 (s, 3, CH₃), 3.06 (m, 2,CH₂), 3.47 (m, 1, CH), 6.48 (s, 1, CH), 7.3 (m, 5, ArH), 7.97 (s, 1,CH).

EXAMPLE 6

3-Methyl-α-(2-phenylpropyl)imidazo[2,1-b]thiazole-5-methanol (FormulaB-5) Refer to Chart B.

A solution of 2-phenylpropyl-3-methylimidazo[2,1-b]thiazol-5-ylmethanone (Formula B-3) (0.28 g) in ethanol (20 mL) was treated withNaBH₄ (41.7 mg) and reacted for 48 hours. Solvent was evaporated and theresidue was treated with water and the precipitated product wasextracted into ethyl acetate. Drying and evaporation of the extract gavecrude 3-Methyl-α-(2-phenylpropyl)imidazo[2,1-b]thiazole-5-methanol(Formula B-5) (0.25 g) which deposited pure3-Methyl-α-(2-phenylpropyl)imidazo[2,1-b]thiazole-5-methanol (FormulaB-5) (0.23 g), m.p. 135-136°, from isopropanol solution.

Anal. Calc'd for C₁₆H₁₈N₂OS: C, 67.10; H, 6.34; N, 9.78; S, 11.20.Found: C, 66.71; H, 5.97; N, 9.30; S, 10.75.

MS m/z 286 (M⁺), 181, 169, 168, 167, 165, and 105.

IR (mull) 3283, 3030, 1493, 1428, 1366, 1302, 1254, 1150, 1094, 1083,and 1035 cm⁻¹.

NMR (CDCl₃) δ 1.36 (d, J=7 Hz, 3, CH₃), 1.8 (b, 1, OH), 2.21 (m, 2,CH₂), 2.38 (s, 3, CH₃), 3.10 (m, 1, CH), 4.65 (m, 1, CH), 6.30 (s, 1,CH), 7.10-7.40 (m, 6, CH, ArH).

PREPARATION 7

(2-Phenylethyl)-3-methylimidazo[2,1-b]thiazol-5-yl methanone (FormulaB-6) Refer to Chart B.

A solution of2-Phenyl-E-ethenyl)-3-methylimidazo[2,1-b]thiazol-5-methanone (FormulaB-2) (0.50 g) in ethylacetate (70 mL) was treated with platinum oxide(0.50 g) at 25° and reduced under 40 psi hydrogen pressure. After 5 daysthe catalyst was filtered and the filtrate was concentrated to an orangeoil (450 g). The oil was loaded onto a silica column (45 gms) andproduce was eluted with 1:3 ethylacetate:hexane to yield pure(2-Phenylethyl)-3-methylimidazo[2,1-]-thiazol-5-yl methanone (FormulaB-6) (0.13 g), m.p. 74-76°, after recrystallization from isopropanol.

Anal. Calc'd for C₁₅H₁₄N₂OS; C, 66.64; H, 5.22; N, 10.36; S, 11.86.Found: C, 66.52; H, 5.24; N, 10.34; S, 11.92.

MS m/z 271, 270 (M⁺), 193, 165, 139, 138, 104, 91, 72, 53, 38

IR (mull) 1661, 1507, 1497, 1429, 1361, 1302, 1184, 1165, 941, 920, 754,747, 696 CM⁻¹.

NMR (CDCl₃) δ 2.74 (s, 3, CH₃), 3.09 (m, 2, CH₂), 3.13 (m, 2, CH₂), 6.51(s, 1, CH), 7.24 (m, 5, ArH), 7.99 (s, 1, CH).

EXAMPLE 7

α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (FormulaB-7) Refer to Chart B.

A solution of (2-Phenylethyl)-3-methylimidazo[2,1-b]thiazol-5-ylmethanone (Formula B-6) (0.40 g) in THF (6 mL) was treated with 3Methereal methyl magnesium bromide (0.6 mL) and reacted for 18 hours. Thesuspension was treated with 5% NH₄Cl solution and precipitatedα,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (FormulaB-7) was extracted into ethyl acetate. The extract was dried andevaporated to a viscous residue which depositedα,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (FormulaB-7) (0.25 g) by ether trituration. Crystallization of the filter cakefrom ethyl acetate gave pureα,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (FormulaB-7) (0.13 g), m.p. 131-133°.

Anal. Calc'd for C₁₆H₁₈N₂OS: C, 67.10; H, 6.34; N, 9.78; S, 11.20.Found: C, 66.44; H, 6.35; N, 9.56; S, 11.08.

MS m/z 286 (M⁺), 271, 183, 182, 181, 165, 139, and 91.

IR (mull) 3169, 3132, 3116, 3106, 3090, 3083, 3062, 3040, 1683, 1655,1605, 1589, 1582, 1499, 1413, 1374, 1355, 1298, 1276, 1266, 1189, and1161 cm⁻¹.

NMR (DMSO) δ 1.7, (s, 3, CH₃), 3.28 (m, 2, CH₂), 2.55 (m, 1, CH₂), 2.72(s, 3, CH₃), 2.80 (m, 1, CH₂), 6.48 (s, 1CH), 7.05-7.35 (m, 5, ArH),7.58 (s, 1, CH).

EXAMPLE 8

3-Methyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (FormulaB-8) Refer to Chart B.

A solution of (2-Phenylethyl)-3-methylimidazo[2,1-b]thiazol-5-ylmethanone (Formula B-6) (0.40 g) in ethanol (5.0 mL) was treated with asolution of NaBH₄ (0.05 g) in ethanol (5 mL) and reacted for 18 hours.The solvent was removed in vacuo and the residue was treated with 5%acetic acid solution. Precipitated3-Methyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (FormulaB-8) (0.38 g) was filtered and recrystallized from isopropanol solutionto provide pure3-Methyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (FormulaB-8) (0.35 g), m.p. 144-145°.

Anal. Calc'd for C₁₅H₁₆N₂OS: C, 66.15; H, 5.92; N, 10.28; S, 11.77.Found: C, 66.07; H, 5.88; N, 10.23; S, 11.74.

MS m/z 272 (M⁺), 168, 167, 139, and 77.

IR (mull) 3236, 3182, 3134, 3116, 1499, 1429, 1160, 1149, 1051, and 915cm⁻¹.

NMR (CDCl₃) δ 2.24 (m, 2, CH₂), 2.55 (s, 3, CH₃), 2.80 (m, 2, CH₂), 3.20(b, 1, OH), 4.88 (t, 1, CH), 6.31 (s, 1, CH), 7.00 (s, 1, CH), 7.23 (m,5, ArH).

PREPARATION 8

2-(4-Bromophenyl)-E-ethenylimidazo[2,1-b]thiazol-5-yl methanone (FormulaB-9) Refer to Chart B.

A solution of 1-(3-methylimidazo[2,1-b]thiazol-5-yl)ethanone (FormulaB-1) (1.8 g) in THF (25 mL) was treated with 4-bromobenzaldehyde (3.05mL) and sodium methoxide (0.27 g) at 25°. Within 5 minutes a heavyprecipitate formed and additional THF (65 mL) was added to maintainfluididy. After 20 minutes the reaction was concentrated in vacuo andthe concentrate was diluted with water and precipitated2-(4-Bromophenyl)-E-ethenylimidazo[2,1-b]thiazole-5-yl methanone(Formula B-9) (2.9 g) was filtered. The precipitate was recrystallizedfrom ethanol to yield pure2-(4-Bromophenyl)-E-ethenylimidazo[2,1-b]thiazol-5-yl methanone (FormulaB-9) (2.8 g, 81%), m.p. 213-215°.

Anal. Calc'd for C₁₅H₁₁BrN₂OS: C, 51.89; H, 3.19; Br, 23.01; N, 8.07; S,9.24. Found: C, 51.90; H, 3.12; Br, 22.86; N, 8.11; S, 9.19.

Ms. m/z 348, 346 (M⁺), 267, 177, 165, 138, 199, 102, 72.

IR (mull) 3121, 1662, 1610, 1513, 1486, 1435, 1428, 1300, 1204, 1198,1035, 1008, 979, 960, 819, 810, 739 cm⁻¹.

NMR (CDCl₃) δ 2.79 (s, 3, CH₃), 6.56 (s, 1, CH), 7.28 (d, J=16 Hz, 2,CH), 7.50 (d, J=8 Hz, 2, ArH), 7.56 (d, J=8 Hz, 2, ArH), 7.70 (d, J=16Hz, 1, CH), 8.15 (S, 1, CH).

PREPARATION 9

2-(4-Bromophenylethyl)-3-methylimidazo[2,1-b]thiazol-5-yl methanone(Formula B-10) Refer to Chart B.

A solution of 2-(4-Bromophenyl)-E-ethenylimidazo[2,1-b]thiazol-5-ylmethanone (Formula B-9) (1.04 g) in toluene (160 mL) was treated with asolution prepared by dissolving Na₂S₂O₄ (14.4 g) in water (220 mL),adding sodium bicarbonate (15.6 g) and Aliquot®336 (0.41 mL). Thevigorously stirred suspension was heated at 100° for 85 hours, dilutedwith ethyl acetate and partitioned. The extract was washed with salinesolutions, dried and evaporated to a viscous residue. The residue waschromatographed on silica gel and product was eluted with 4:1hexane:ethyl acetate to provide2-(4-Bromophenylethyl)-3-methylimidazo[2,1-b]thiazol-5-yl methanone(Formula B-10) (0.220 g). An aliquot was crystallized from isopropanolto yield pure 2-(4-Bromophenylethyl)-3-methylimidazo[2,1-b]thiazol-5-ylmethanone (Formula B-10), m.p, 113-115°.

MS m/z 350, 348 (M⁺), 333, 331, 319, 317, 268, 239, 193, 191, 185, 184,183, 182, 165, 139, and 138.

IR (mull) 1662, 1506, 1487, 1425, 1402, 1362, 1352, 1304, 1270, 1188,1182, 1170, 1072, 1008 and 939 cm⁻¹.

NMR (CDCl₃) δ 2.73 (s, 3, CH₃), 3.04 (m, 2, CH₂), 3.10 (m, 2, CH₂), 6.51(s, 1, CH), 7.11 (d, J=8 Hz, 2, ArH), 7.40 (d, J=8 Hz, 2, ArH), 7.99 (s,1, CH).

EXAMPLE 9

3-Methyl-α-(4-bromophenylethyl)imidazo[2,1-b]thiazole-5-methanol(Formula B-11) Refer to Chart B.

A solution of 2-(4-Bromophenylethyl)-3-methylimidazo[2,1-b]thiazol-5-ylmethanone (Formula B-10) (0.2 g) in ethanol (5 mL) was treated with asolution of NaBH₄ (65 mg) in ethanol (5 mL) and reacted for 3 hours. Thesolution was evaporated, the residue was diluted with water andprecipitated3-Methyl-α-(4-bromophenylethyl)imidazo[2,1-b]thiazole-5-methanol(Formula B-11) (0.20 g) was filtered. Crystallization from acetonitrilegave pure3-Methyl-α-(4-bromophenylethyl)imidazo[2,1-b]thiazole-5-methanol(Formula B-11), m.p. 175-178°.

Anal. Calc'd for C₁₅H₁₅N₂OS: C, 51.29; H, 4.30; Br, 22.75; N, 7.98; S,9.13. Found: C, 51.41; H, 4.31; Br, 22.44; N, 8.01; S, 9.14.

MS m/z 352, 350 (M⁺), 169, 168, 167, 139, 109, and 90.

IR (mull) 3244, 3184, 3078, 1665, 1647, 1571, 1536, 1451, 1490, 1448,1430, 1308, 1288, 1178, 1141, 1075, and 1044 cm⁻¹.

NMR (CDCl₃) δ 2.27 (m, 2, CH₂), 2.58 (s, 3, CH₃), 2.80 (m, 2, CH₂), 4.88(t, 1, CH), 6.38 (s, 1, CH), 7.09 (d, J=8 Hz, 2, ArH), 7.15 (s, 1, CH),7.41 (d, J=8 Hz, 2, ArH).

PREPARATION 10

N′-(4-Methyl-2-thiazolyl)-N,N-dimethyl-methanimidamide (Formula C-2)Refer to Chart C.

A solution 2-amino-4-methylthiazole (Formula C-1)(11.4 g) in toluene(100 ml) at 25° was treated with dimethylformamide dimethyl acetal (15.9mL, 200 mmol), dropwise over five minutes. The mixture was heated toreflux temperature for 22 hours. The reaction was cooled to 25° and thesolvent evaporated to an orange oil (17 g). The oil was triturated withhexane to yield yellow crystals. Recrystallization from warm hexane gaveN′-(4-Methyl-2-thiazolyl)-N,N-dimethyl-methanimidamide (Formula C-2)(16.9 g, 99.6%), m.p. 54-56°.

Anal. Calc'd for C₇H₁₁N₃S: C, 49.68; H, 6.55; N, 24.83; S, 18.94. Found:C, 49.71; H, 6.64; N, 24.52; S, 18.70.

MS m/z 169 (M⁺), 154, 136, 127, 99, 98, 71, 44, and 27.

IR (mull) 3081, 1632, 1503, 1475, 1431, 1414, 1398, 1354, 1302, 1265,1133, and 1117 cm⁻¹.

NMR (CDCl₃) δ 2.30 (s, 3, CH₃), 3.06 (s, 3, CH₃), 3.08 (s, 3, CH₃), 6.34(s, 1, CH), 8.18 (s, 1, CH).

PREPARATION 11

2-[[(Dimethylamino)methylene]amino]-3-)2-ethoxy-2-oxoethyl)-4-methyl-thiazoliumbromide (Formula C-3) (Refer to Chart C).

Solid N′-(4-Methyl-2-thiazolyl)-N,N-dimethyl-methanimidamide (FormulaC-2) (5.0 g) was added in portions to vigorously stirred ethylbromoacetate (16 mL). Precipitation of2-[[(Dimethylamino)methylene]amino]-3-)2-ethoxy-2-oxoethyl)-4-methyl-thiazoliumbromide (Formula C-3) was well advanced after 2 hours and toluene (10mL) was added to improve fluidity. After 24 hours the precipitated2-[[(Dimethylamino)methylene]amino]-3-)2-ethoxy-2-oxoethyl)-4-methyl-thiazoliumbromide (Formula C-3) (9.8 g) was filtered and crystallized fromacetonitrile to yield pure2-[[(Dimethylamino)methylene]amino]-3-)2-ethoxy-2-oxoethyl)-4-methyl-thiazoliumbromide (Formula C-3), 8.32 g, m.p. 188-189°. HeatingN′-(4-Methyl-2-thiazolyl)-N,N-dimethyl-methanimidamide (Formula C-2) intoluene solution for 4.5 hours with a 20% molar excess of ethylbromoacetate also gave2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-4-methyl-thiazoliumbromide (Formula C-3) (76%) cleanly.

Anal. Calc'd for C₁₁H₁₈BrN₃O₂S: C, 39.29; H, 5.39; Br, 23.77; N, 12.50;S 9.53. Found: C, 39.34; H, 5.36; Br, 23.78; N, 12.52; S, 9.48.

MS (FAB) m/z 256 (M⁺-Br).

IR (mull) 3028, 1757, 1645, 1593, 1531, 1491, 1481, 1419, 1402, 1393,1218, and 1138 cm⁻¹.

NMR (CDCl₃) δ 1.30 (t, J=7 Hz, 3, CH₃), 2.41 (s, 3, CH₃), 3.23 (s, 3,CH₃), 3.60 (s, 3, CH₃), 4.25 (q, J=7 Hz, 2, CH₂), 4.98 (s, 2, CH₂), 6.86(s, 1, CH), 9.32 (s, 1, CH).

PREPARATION 12

3-Methylimidazo[2,1-b]thiazole-5-carboxylic acid ethyl ester (FormulaC-4) Refer to Chart C.

A solution of2-[[(Dimethylamino)methylene]amino]-3-)2-ethoxy-2-oxoethyl)-4-methyl-thiazoliumbromide (Formula C-3) (6.5 g) in DMF (20 mL) was treated with DBU (5.78g) and reacted for 24 hours. The reaction solution was diluted withwater and precipitated 3-Methylimidazo[2,1-b]thiazole-5-carboxylic acidethyl ester (Formula C-4) (2.1 g) was filtered. Crystallization fromhexane gave pure 3-Methylimidazo[2,1-b]thiazole-5-carboxylic acid ethylester (Formula C-4), m.p. 45°.

Anal. Calc'd for C₉H₁₀N₂O₂S: C, 51.41; H, 4.79; N, 13.33; S, 15.25.Found: C, 51.32; H, 4.78; N, 13.23; S, 15.14.

MS m/z 210 (M⁺), 182, 181, 165, 164, 138, 136, 125, and 93.

IR (mull) 1723, 1507, 1440, 1434, 1425, 1353, 1318, 1207, 1195, 1140,1083, 1074 and 1070 cm⁻¹.

NMR (CDCl₃) 1.38 (t, J=7 Hz, 3, CH₃), 2.73 (s, 3, CH₃), 4.32 (q, J=7 Hz,2, CH₂), 6.50 (s, 1, CH), 7.98 (s, 1, CH)

PREPARATION 13

3-Methylimidazo[2,1-b]thiazole-5-Methanol (FIG. C-5) Refer to Chart C.

A solution of 3-Methylimidazo[2,1-b]thiazole-5-carboxylic acid ethylester (Formula C-4) (1.93 g, 9.2 mmol) in dry THF (20 ml) at 0° wastreated with LiAlH₄ (12.3 mmols, 0.47 gms) and reacted at 25° for 2hours. The reaction was quenched by serial additions of 2% aqueous.. THF(24 mL), 15% NAOH (0.47 mL), and 2% aqueous THF (1.5 mL). The suspensionwas filtered and the filtrate was concentrated to a white solid (1.48gm). The solid was recrystallized from isopropanol to yield pure3-Methylimidazo[2,1-b]thiazole-5-Methanol (FIG. C-5) (1.18 g), m.p.161-162°.

Anal. Calc'd for C₇H₈N₂OS: C, 49.98; H, 4.79; N, 16.65; S, 19.06. Found:C, 49.87; H, 4.80; N, 16.48; S, 18.91.

MS m/z 168 (M⁺), 167, 152, 151, 150, 139, 72, 71, 45.

IR (mull) 3140, 3123, 3098, 2749, 1446, 1431, 1390, 1340, 1314, 1144,1029, 1023, 1016, 828, 821, 754, 689, 650 cm⁻¹.

NMR (DMSO, D₆) δ 3.33 (S, 3, CH₃), 4.70 (d, J=5 Hz, 2, CH₂), 5.16 (t,J=5 Hz, 1, OH), 6.54 (s, 1, CH), 7.11 (s, 1, CH).

PREPARATION 14

3-Methylimidazo[2,1-b]thiazole-5-carboxaldehyde (FIG. C-6) Refer toChart C.

A solution of 3-Methylimidazo[2,1-b]thiazole-5-methanol (FIG. C-5) (0.9g) in DMF (10 mL) was diluted with toluene (200 mL), treated with MnO₂(3.0), and azeotropically distilled for 1.5 hours. The suspension wasfiltered and the filtrate was concentrated to 10 mL. The concentrate wasdiluted with ice water and the precipitated3-Methylimidazo[2,1-b]thiazole-5-carboxaldehyde (FIG. C-6) (0.665 g) wasfiltered. An aliquot (225 mg) was recrystallized from ethylacetate-hexane to yield pure3-Methylimidazo[2,1-b]thiazole-5-carboxaldehyde (FIG. C-6) (202 mg),m.p. 163-165°.

Anal. Calc'd for C₇H₆N₂OS; C, 50.59; H, 3.64; N, 16.85; S, 19.29. Found:C, 50.63; H, 3.64; N, 16.70; S, 18.95.

MS m/z 166 (M⁺), 165, 137, 93, 72, 71, 70, 45, 38.

IR (mull) 3104, 3053, 3016, 1677, 1671, 1451, 1394, 1353, 1323, 1309,1262, 1174, 833, 798 cm⁻¹.

NMR (CDCl₃) δ 2.79 (s, 3, CH₃), 6.56 (s, 1, CH), 8.02 (s, 1, CH), 9.61(s, 1, CH).

EXAMPLE 10

3-Methyl-α-(4-phenylbutyl)imidazo-[2,1-b]thiazole-5-methanol (FIG. C-7)Refer to Chart C.

Magnesium (0.15 g) in ether (15 mL) was treated with1-bromo-4-phenylbutane (prepared by the procedure described in Kamijo etal., Chem. Phar. Bull., 1983, 31, 4189) (1.50 g) at 0° and the mixturewas reacted at 25° for 2.5 hours. The suspension was cooled to 0°, solid3-Methylimidazo[2,1-b]thiazole-5-carboxaldehyde (FIG. C-6) (0.332 g) wasadded and the mixture was reacted at 25° for 3 hours. The solution wasdecanted into 5% NH₄Cl solution and extracted with ethyl acetate. Theextract was dried, evaporated and the residue (0.55 g) was crystallizedfrom acetonitrile solution to yield pure3-Methyl-α-(4-phenylbutyl)imidazo-[2,1-b]thiazole-5-methanol (FIG. C-7)(0.39 g), m.p. 120-121°.

Anal. Calc'd for C₁₇H₂₀N₂OS: C, 67.97; H, 6.71; N, 9.32; S, 10.67.Found: C, 67.67; H, 6.68; N, 9.28; S, 10.56.

MS m/z 300 (M⁺), 169, 168, 167, 139, 138, 114, and 91.

IR (mull) 3161, 3145, 3132, 3082, 3063, 3031, 3019, 1495, 1450, 1309,1260, 1148, 1070, and 956 cm⁻¹.

NMR (CDCl₃) δ 1.71 (m, 3, CH₃), 2.00 (m, 3, CH₂), 2.63 (m, 5, CH₂) 4.9(t, 1, CH), 6.36 (s, 1, CH), 7.11 (s, 1, CH), 7.20 (m, 5, ArH).

PREPARATION 15

2,3-Dimethyl-(2-phenyl-E-ethenyl)imidazo[2,1-b]thiazol-5-yl methanone(FIG. D-2) Refer to Chart D.

A solution of 1-(2,3-dimethylimidazo[2,1-b]thiazole-5-yl ethanone (Seeprocedures from Preparation 6) (Formula D-1) (0.87 g) in THF (25 mL) wastreated with benzaldehyde (0.52 mL) and sodium methoxide (0.11 g). After18 hours trace 1-(2,3-dimethylimidazo[2,1-b]thiazol-5-yl ethanoneremained and additional benzaldehyde (0.2 mL) was added. After anadditional 2.5 hours the reaction was diluted with ice water andprecipitated 2,3-Dimethyl-(2-phenyl-E-ethenyl)imidazo[2,1-b]thiazol-5-ylmethanone (FIG. D-2) (1.03 g) was filtered. Crystallization fromisopropanol solution gave pure2,3-Dimethyl-(2-phenyl-E-ethenyl)imidazo[2,1-b]thiazol-5-yl methanone(FIG. D-2), m.p. 189-190°.

Anal. Calc'd for C₁₆H₁₄N₂OS: C, 68.06; H, 5.00; N, 9.92; S, 11.36.Found: C, 68.05; H, 5.06; N, 9.85, S, 11.26.

MS m/z 282 (M⁺), 265, 254, 253, 241, 239, 205, 191, 179, 154, 153, 152,127, and 103.

IR (mull) 3096, 1658, 1601, 1577, 1506, 1450, 1421, 1360, 1308, 1296,1279, 1200, 1189, 1179, 1034, and 1025 cm⁻¹.

NMR (CDCl₃) δ 2.39 (s, 3, CH₃), 2.68 (s, 3, CH₃), 7.30 (d, J=16 Hz, 1,CH), 7.42 (m, 3, ArH), 7.62 (m, 2, ArH), 7.79 (d, J=16 Hz, 1, CH), 8.09(s, 1, CH).

EXAMPLE 11

2,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (FIG.D-4) Refer to Chart D.

A solution of2,3-Dimethyl-(2-phenyl-E-ethenyl)imidazo[2,1-b]thiazol-5-yl methanone(FIG. D-2) (0.3 g) in 5:3 ethylacetate:ethanol solution (50 mL) wastreated with PtO₂ (0.15 g) and reduced at 45 psi H₂ pressure for 24hours. The catalyst was filtered, the reaction was recharged with PtO₂(0.15 g) and reduced for an additional 24 hours. Catalyst was filteredand solvents evaporated to yield a viscous residue. Ether trituration ofthe residue provide 0.15 g of a 2:1 mixture of starting material and(2-phenylethyl-2,3-dimethylimidazo[2,1-b]thiazol-5-yl methanone (FormulaD-3). The ether filtrate residue (0.15 g) was rich in(2-phenylethyl-2,3-dimethylimidazo[2,1-b]thiazol-5-yl methanone (FormulaD-3) and was reduced to2,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (FIG.D-4) in ethanol (10 ml) solution with NaBH₄ (0.15 g) during 30 minutes.The residue from evaporation of ethanol was treated with water and thesticky precipitate was extracted into ethyl acetate. Drying andevaporation of the extract gave crude2,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (FIG.D-4) which was purified on silica gel (100 g) with 1:1 ethylacetate:hexane. Crystallization of the eluted product from ethyl acetategave pure2,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (FIG.D-4), m.p. 153-154°.

Anal. Calc'd for C₁₆H₁₈N₂OS: C, 67.10; H, 6.34; N, 9.78; S, 11.19.Found: C, 67.17; H, 6.30; N, 9.79: S, 11.10.

MS m/z 286 (M⁺) 259, 242, 203, 181, 165, and 153.

IR (mull) 3245, 1640, 1603, 1487, 1449, 1393, 1328, 1244, 1138, 1063,and 1052 cm⁻¹.

NMR (CDCl₃) δ 2.30 (m, 5, CH₃, CH₂), 2.47 (s, 3, CH₃), 2.75-3.0 (m, 2,CH₂), 4.90 (t, 1, CH), 7.14 (s, 1, CH), 7.18-7.35 (m, 5, ArH).

EXAMPLE 12

2,3-Dimethyl-α-(2-phenylethenyl)imidazo[2,1-b]thiazole-5-methanol (FIG.D-5) Refer to Chart D.

A solution of2,3-Dimethyl-α-(2-phenyl-E-ethenyl)imidazo[2,1-b]thiazole-5-methanone(FIG. D-2) (0.34 g) in 1:1 ethanol:THF (40 mL) was treated with asolution of NaBH₄ (0.35 g) in ethanol (5 mL). The solution was reactedfor 2.5 hours, evaporated in vacuo, and the residue was diluted withwater. The precipitated2,3-Dimethyl-α-(2-phenylethenyl)imidazo[2,1-b]thiazole-5-methanol (FIG.D-5) was extracted into ethyl acetate, the extract was dried andevaporated to a viscous residue. The residue was triturated with ethylacetate to yield2,3-Dimethyl-α-(2-phenylethenyl)imidazo[2,1-b]thiazole-5-methanol (FIG.D-5), 0.28 g, m.p. 149-151° after crystallization from acetonitrile.

Anal. Calc'd for C₁₆H₁₆N₂OS: C, 67.58; H, 5.67; N, 9.85; S, 11.27.Found: C, 67.20; H, 5.84; N, 9.74; S, 11.05.

MS m/z 284, 267, 255, 207, 181, 179, 165, 153, 152, 139, 128, 115 and103.

IR (mull) 3240, 3119, 3025, 1651, 1641, 1626, 1603, 1497, 1442, 1426,1327, 1323, 1308, 1244 and 1140 cm⁻¹.

NMR (CDCl₃) δ 2.28 (s, 3, CH₃), 2.57 (s, 3, CH₃), 5.68 (d, J=5 Hz, 1,CH), 6.53 (q, J=5, 16 Hz, 1, CH), 6.75 (d, J=16 Hz, 1, CH), 6.98 (s, 1,CH), 7.17-7.50 (m, 5, ArH).

PREPARATION 16

N′-(5,6-Dihydro-4H-cyclopentathiazolyl)-N,N-dimethylmethimidamide(Formula E-2) Refer to Chart E.

A suspension of 2-aminocyclopentenothiazole (Formula E-1) (8.9 g) intoluene (15 mL) and DMF-dimethylacetal (15.4 mL) was reacted at ambienttemperature for 72 hours. The solution was diluted with toluene (150mL), treated with charcoal, and filtered. The filtrate was evaporated toa crystalline residue (14.7 g) and the residue was triturated withhexane to yieldN′-(5,6-Dihydro-4H-cyclopentathiazolyl)-N,N-dimethylmethimidamide(Formula E-2) (11.62 g) as two crops. Crystallization of an aliquot(1.31 g) from ether-hexane solution gave the analytical sample ofN′-(5,6-Dihydro-4H-cyclopentathiazolyl)-N,N-dimethylmethimidamide(Formula E-2) (1.07 g), m.p. 124-125°.

Anal. Calcd for C₉H₁₃N₃S: C, 55.35; H, 6.72; N, 21.52; S, 16.42. Found:C, 55.45; H, 6.88; N, 21.85; S, 16.49.

MS m/z 195 (M⁺), 180, 162, 153, 147, 115, and 97.

IR (mull): 1614, 1484, 1448, 1443, 1427, 1401, 1360, 1339 and 1093 cm⁻¹.

NMR (CDCl₃) δ 2.36 (m, 2, CH₂), 2.74 (m, 2, CH₂), 2.83 (m, 2, CH₂), 3.06(s, 3, CH₃), 3.08 (s, 3, CH₃), 8.24 (s, 1, CH).

PREPARATION 17

2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6-dihydro-4H-cyclopentathiazoliumbromide (Formula E-3) Refer to Chart E.

A suspension ofN′-(5,6-Dihydro-4H-cyclopentathiazolyl)-N,N-dimethylmethimidamide(Formula E-2) (2.40 g) in ethyl bromoacetate (9.0 mL) was dissolved byheating at 45°. Precipitation occurred and additional reagent (5.0 mL)was added. The suspension was reacted for 72 hours, diluted with ethylacetate, and filtered to yield2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6-dihydro-4H-cyclopentathiazoliumbromide (Formula E-3) (4.38 g). The thiazolium salt was used withoutfurther purification.

PREPARATION 18

6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxylic acidethyl ester (Formula E-4) Refer to Chart E.

A suspension of2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6-dihydro-4H-cyclopentathiazoliumbromide (Formula E-3) (4.0 g) in DMF (20 mL) dissolved on addition ofDBU (2.48 mL). The solution was reacted at 25° for 18 hours, poured intocold 10% acetic acid solution, and precipitated6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxylic acidethyl ester (Formula E-4) (1.95 g) was filtered. Crystallization of analiquot from isopropanol gave pure6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxylic acidethyl ester (Formula E-4), m.p. 101-102°.

Anal. Calcd for C₁₁H₁₂N₂O₂S: C, 55.92; H, 5.12; N, 11.86; S, 13.57 .Found: C, 55.85; H, 4.98; N, 11.80; S, 13.57.

MS m/z 236 (M⁺), 221, 207, 191, 190, 189, 177, 164, 163, 162, 136, 135,134, and 97.

IR (mull) 1712, 1525, 1509, 1447, 1403, 1393, 1348, 1311, 1287, 1191,1135, 1111, 1051, and 1023 cm⁻¹.

NMR (CDCl₃) δ 1.38 (t, J=7 Hz, 3, CH₃), 2.51 (m, 2, CH₂), 2.93 (m, 2,CH₂), 3.27 (m, 2, CH₂), 4.33 (q, J=7 Hz, 2, CH₂), 7.87 (s, 1, CH).

PREPARATION 19

6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol (FIG. E-5)Refer to Chart E.

A solution of6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxylic acidethyl ester (Formula E-4) (5.8 g) in dry THF (125 mL) was treated withLiAlH₄ (1.86 g) and reacted for 5.5 hours. After serial quenching withwater and 15% sodium hydroxide, the suspension was diluted to 700 mLwith chloroform. The filter cake was washed with hot chloroform, thecombined filtrate and washes were evaporated to yield pure6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol (FIG. E-5)(2.67 g).

NMR (DMSO) δ 2.43 (m, 2, CH₂), 2.83 (m, 2, CH₂), 2.97 (m, 2, CH₂), 4.56(d, J=5 Hz, 2, CH₂) 5.21 (t, J=5 Hz, 1, OH), 7.04 (s, 1, CH).

PREPARATION 20

6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxaldehyde (FIG.E-6) Refer to Chart E.

A solution of6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol (FIG. E-5)(1.5 g) in DMF (20 mL) was diluted with toluene (125 mL), treated withactivated manganese dioxide, and the mixture was azeotropicallydistilled for 60 minutes. The hot solution was filtered and the filtratewas concentrated. The residue was diluted with water and precipitated6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxaldehyde (FIG.E-6) (1.28 g) was filtered. The carboxaldehyde was used without furtherpurification.

NMR (CDCl₃) δ 2.54 (m, 2, CH₂), 2.95 (m, 2, CH₂), 3.32 (m, 2, CH₂), 7.91(s, 1, CH), 9.62 (s, 1, CH).

EXAMPLE 13

6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol(FIG. E-7) Refer to Chart E

The Grignard reagent generated during 18 hours, from(2-bromoethyl)benzene (2.2 g) an Mg (0.291 g) in THF (70 mL) was treatedwith solid6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxaldehyde (FIG.E-6) (0.58 g) and reacted for 1.5 hours. The supernate solution wasdecanted into cold 5% ammonium chloride solution and precipitated6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol(FIG. E-7) (0.80 g) was filtered. Crystallization from acetonitrilesolution gave pure6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol(FIG. E-7), m.p. 117-118°.

Anal. calcd for C₁₇H₁₈N₂OS: C, 68.43; H, 6.08; N, 9.39; S, 10.74. Found:C, 68.21; H, 6.02; N, 9.21; S, 10.53.

MS m/z 298 (M⁺), 281, 271, 254, 218, 207, 206, 193, 177, 175, 165, 129,and 91.

IR (mull) 3222, 3125, 3088, 3059, 3032, 3029, 1615, 1605, 1497, 1361,1347, 1333, 1297, 1289, 1281, and 1073.

NMR (CDCl₃) δ 2.22 (m, 2, CH₂), 2.50 (m, 3, CH₂, OH), 2.74-3.10 (m, 6,CH₂), 4.80 (t, J=5 Hz, 1, CH), 6.99 (s, 1, CH), 7.29-7.4 (m, 5, ArH).

PREPARATION 21

N′-(4,5,6,7-Tetrahydrobenzothiazolyl)-N,N-dimethylmethimidamide (FormulaF-2) Refer to Chart F.

A solution of 2-amino-4,5,6,7-tetrahydrobenzothiazole (Formula F-1)(5.48 g) in toluene (70 mL) was treated with DMF-dimethylacetal (9.43mL) and heated at reflux temperature for 1.5 hours. The cooled solutionwas evaporated in vacuo to a crystalline residue. The residue wastriturated with hexane to provideN′-(4,5,6,7-Tetrahydrobenzothiazolyl)-N,N-dimethylmethimidamide (FormulaF-2) (4.33 g). The filtrate residue (1.9 g) was filtered through silicagel (100 g) with 1:1 ethyl acetate hexane to yield additionalN′-(4,5,6,7-Tetrahydrobenzothiazolyl)-N,N-dimethylmethimidamide (FormulaF-2) (1.26 g). An aliquot of elutedN′-(4,5,6,7-Tetrahydrobenzothiazolyl)-N,N-dimethylmethimidamide (FormulaF-2) was crystallized from ether hexane solution to provide pureN′-(4,5,6,7-tetrahydrobenzothiazolyl)-N,N-dimethylmethimidamide (FormulaF-2), m.p. 96-97°.

Anal. Calcd for C₁₀H₁₅N₃S: C, 57.38; H, 7.22; N, 20.08; S, 15.32. Found:C, 57.45; H, 7.16; N, 20.08; S, 15.16.

MS m/z 209, 194, 193, 181, 176, 167, 139, 115, and 98.

IR (mull): 1623, 1567, 1510, 1478, 1426, 1411, 1396, 1356, 1347, 1330,1262, and 1113 cm⁻¹.

NMR (CDCl₃) δ 1.82 (m, 4, CH₂), 2.62 (m, 4, CH₂), 3.05 (s, 3, CH₃), 3.07(s, 3, CH₃), 8.14 (s, 1, CH).

PREPARATION 22

2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6,7,8-tetrahydrobenzothiazoliumbromide (Formula F-3) Refer to Chart F.

A solution of crudeN′-(4,5,6,7-Tetrahydrobenzothiazolyl)N,N-dimethylmethimidamide (FormulaF-2) (9.38 g) in ethyl bromoacetate (45 mL) produced a thick precipitateof the thiazolium salt (Formula F-3) within 1.5 hours. The suspensionwas diluted to 500 mL with ethyl acetate, filtered under a N₂atmosphere, and dried in vacuo to yield crude thiazolium salt (FormulaF-3) as a hygroscopic solid (14.4 g). The precipitated2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6,7,8-tetrahydrobenzothiazoliumbromide (Formula F-3) was used without additional purification.

PREPARATION 23

5,6,7,8-Tetrahydro-imidazo[2,1-b]benzothiazole-3-carboxylic acid ethylester (Formula F-4) Refer to Chart F.

A solution of crude2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6,7,8-tetrahydrobenzothiazoliumbromide (Formula F-3) (14.4 g) in DMF (40 mL) was treated with DBU (8.4mL) and reacted at ambient temperature for 24 hours. The solution wasdiluted with ice water and acidified with 1N hydrochloric acid (58 mL).The precipitated5,6,7,8-Tetrahydro-imidazo[2,1-b]benzothiazole-3-carboxylic acid ethylester (Formula F-4) (5.61 g, 63%) was filtered. Crystallization fromhexane gave pure5,6,7,8-Tetrahydro-imidazo[2,1-b]benzothiazole-3-carboxylic acid ethylester (Formula F-4), m.p. 75-76°.

Anal. Calcd for C₁₂H₁₄N₂O₂S: C, 57.58; H, 5.64; N, 11.19; S, 12.81.Found: C, 57.59; H, 5.82; N, 11.17; S, 12.82.

MS m/z 250 (M⁺) 222, 221, 205, 204, 203, 178, 176, 175, and 150.

IR (mull) 1720, 1515, 1505, 1451, 1435, 1312, 1292, 1257, 1194, 1174,1162, 1126, 1112, and 1027 cm⁻¹.

NMR (CDCl₃) 1.37 (t, J=7 Hz, 3, CH₃), 1.91 (m, 4, CH₂), 2.74 (m, 2,CH₂), 3.17 (m, 2, CH₂), 4.31 (q, J=7 Hz, 2, CH₂), 7.94 (s, 1, CH).

PREPARATION 24

5,6,7,8-Tetrahydro-imidazo[2,1-b]benzothiazole-3-methanol (Formula F-5)Refer to Chart F.

A suspension of LiAlH₄ (2.1 g) in THF (100 mL) was treated with5,6,7,8-Tetrahydro-imidazo[2,1-b]benzothiazole-3-carboxylic acid ethylester (Formula F-4) (5.6 g) and reacted at 25° C. for 5.5 hours. Thereaction was quenched by serial additions of water and 15% sodiumhydroxide and the mixture was filtered. Evaporation of the filtrate gave5,6,7,8-Tetrahydro-imidazo[2,1-b]benzothiazole-3-methanol (Formula F-5)(4.11 g), m.p. 182-183° after crystallization from iso-propanol.

Anal. Calcd for C₁₀H₁₂N₂OS: C, 57.67; H, 5.81; N, 13.45; S, 15.39.Found: C, 57.44; H, 5.78; N, 13.26; S, 15.36. MS m/z 208 (M⁺), 191, 190,189, 179, 163, 132 and 77 IR (mull) 3179, 3095, 1630, 1446, 1442, 1357,1321, 1312, 1258, and 1026 cm⁻¹. NMR (CDCl₃) 1.91 (m, 4, CH₂), 2.67 (m,2, CH₂), 2.99 (m, 2, CH₂), 3.07 (s, 1, OH), 4.73 (s, 2, CH₂), 6.99 (s,1, CH).

PREPARATION 25

5,6,7,8-Tetrahydro-imidazo[2,1-b]thiazole-3-carboxaldehyde (Formula F-6)Refer to Chart F.

A solution of 5,6,7,8-Tetrahydro-imidazo[2,1-b]benzothiazole-3-methanol(Formula F-5) (3.9 g) in hot toluene (270 mL) was treated with activatedMnO₂ (11.7 g) and azetropically distilled for 1.5 hours. The cooledsuspension was filtered and the filtrate was evaporated to yield pure5,6,7,8-Tetrahydro-imidazo[2,1-b]thiazole-3-carboxaldehyde (Formula F-6)(3.27 g) after hexane trituration. Crystallation of an aliquot fromiso-propanol provided an analytical sample, m.p. 108-110°.

Anal. Calcd for C₁₀H₁₀N₂OS: C, 58.25; H, 4.89; N, 13.58; S, 15.54.Found: C, 58.19; H, 4.70; N, 13.79; S, 15.42. MS m/z 206 (M⁺), 205, 191,189, 178, 177, 165, 163 and 150. IR (mull) 3096, 1674, 1661, 1445, 1362,1355, and 1172 cm⁻¹. NMR (CDCl₃) δ 1.91 (m, 4, CH₂), 2.73 (m, 2, CH₂),3.18 (m, 2, CH₂), 7.95 (s, 1, CH), 9.56 (s, 1, CH).

EXAMPLE 14

5,6,7,8-Tetrahydro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol(Formula F-7) Refer to Chart F.

A suspension of Mg (0.31 g) in ether (50 mL) was treated with(2-bromoethyl)benzene (1.32 mL) and reacted for 1.5 hours. Solid5,6,7,8-Tetrahydro-imidazo [2,1-b]thiazole-3-carboxaldehyde (FormulaF-6) (0.66 g) was added, the suspension was diluted with THF (100 mL)and reacted for 18 hours. The supernate solution was decanted into 5%ammonium chloride solution (200 mL) and extracted with ethyl acetate.Drying and evaporation of solvent gave5,6,7,8-Tetrahydro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol(Formula F-7) (0.88 g) which deposited pure5,6,7,8-Tetrahydro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol(Formula F-7) (0.74 g), m.p. 152-153°, from acetonitrile solution.

Anal. Calcd for C₁₈H₂₀N₂OS: C, 69.20; H, 6.45; N, 8.97; S, 10.26. Found:C, 68.90; H, 6.59; N, 8.94; S, 10.22. MS m/z 312 (M⁺), 295, 285, 268,208, 207, 191, 189, 179, 165, 151, 129, and 91. IR (mull) 3185, 3135,3091, 3067, 3059, 3032, 3025, 1604, 1500, 1446, 1431, 1314, 1274, 1259,1152, 1076 and 1055 cm⁻¹. NMR (CDCl₃) δ 1.88 (m, 4, CH₂), 2.26 (m, 2,CH₂), 245 (b, 1, OH), 2.55-3.0 (m, s, CH₂), 3.20 (m, 1, CH₂), 4.85 (t,J=5 Hz, 1, CH), 7.06 (s, 1, CH), 7.15-7.40 (m, s, ArH).

PREPARATION 26

N′-(5,6,7,8-Tetrahydro-4H-cycloheptathiazolyl)-N,N-dimethylmethimidamide(Formula G-2) Refer to Chart G.

A solution of 2-aminocycloheptenothiazole (Formula G-1)(13.0 g) intoluene (125 mL) was treated with DMF-dimethylacetal (12.2 mL), heatedat reflux temperature for 18 hours, and reacted at 25° for 18 hours.Evaporation in vacuo gave a crystalline mass ofN′-(5,6,7,8-Tetrahydro-4H-cycloheptathiazolyl)-N,N-dimethylmethimidamide(Formula G-2) which was recrystallized from cold hexane solution toprovide pureN′-(5,6,7,8-Tetrahydro-4H-cycloheptathiazolyl)-N,N-dimethylmethimidamide(Formula G-2) (14.82 g), m.p. 46-48°.

Anal. Calcd for C₁₁H₁₇N₃S: C, 59.16; H, 7.67; N, 18.82; S, 14.36. Found:C, 58.78; H, 7.74; N, 18.96; S, 14.11. MS m/z 223 (M⁺), 208. 207, 195,194, 190, 181, 167, 153, 136, 115, and 98. IR (mull): 1617, 1488, 1429,1340, 1179, 1105 and 1191 cm⁻¹. NMR (CDCl₃) δ 1.6-1.85 (m, 6, CH₂), 2.66(m, 2, CH₂), 2.79 (m, 2, CH₂) 3.04 (s, 3, CH₃) 3.18 (s, 3, CH₃), 8.08(s, 1, CH).

PREPARATION 27

2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6,7-tetrahydro-4H-cycloheptathiazoliumbromide (Formula G-3) Refer to Chart G.

A solution ofN′-(5,6,7,8-Tetrahydro-4H-cycloheptathiazol-N,N-dimethylmethimidamide(Formula G-2) (14.8 g) in ethyl bromoacetate (25 mL) was reacted at 25°for 72 hours. The suspension of2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6,7-tetrahydro-4H-cycloheptathiazoliumbromide (Formula G-3) was diluted with ethyl acetate (75 mL), filtered,and the filter cake was dried in vacuo to yield pure2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6,7-tetrahydro-4H-cycloheptathiazoliumbromide (Formula G-3) (24.3 g), m.p. 155-158°.

Anal. Calcd for C₁₅H₂₄BrN₃O₂S: C, 46.16; H, 6.20; Br, 20.47; N, 10.76;S, 8.21. Found: C, 45.84; H, 6.14; Br, 20.74; N, 10.70; S, 8.14. MS(FAB) m/z 310 (M⁺−Br) IR (mull) 3200-3500, 1638, 1601, 1513, 1483, 1422,1407, 1392, 1290, and 1212 cm⁻¹. NMR (CDCl₃) δ 1.30 (t, J=7.2 Hz, 3CH₃), 1.65-1.95 (m, 6, CH₂), 2.65 (m, 2, CH₂), 2.76 (m, 2, CH₂), 3.17(s, 3, CH₃), 3.61 (s, 3, CH₃), 4.26 (q, J=7.2 Hz, 2, CH₂), 4.92 (s, 2,CH₂), 9.49 (s, 1, CH).

PREPARATION 28

6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-carboxylicacid ethyl ester (Formula G-4) Refer to Chart G.

A solution of2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-2-oxoethyl)-5,6,7-tetrahydro-4H-cycloheptathiazoliumbromide (Formula G-3)(21.3 g) in DMF (80 mL) was treated with DBU (16.3mL) and reacted for 72 hours. The solution was diluted with ice-water(400 mL) and precipitated6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-carboxylicacid ethyl ester (Formula G-4)(11.7 g) was filtered. Crystallization ofan aliquot of the precipitate from ethyl acetate-hexane solution gavepure6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-carboxylicacid ethyl ester (Formula G-4), m.p. 73-74°.

Anal. Calcd for C₁₃H₁₆N₂O₂S: C, 59.07; H, 6.10; N, 10.60; S, 12.13;Found: C, 58.78; H, 6.17; N, 10.59; S, 12.03. MS m/z 264 (M⁺), 249, 235,219, 218, 217, 192, 190, and 91. IR (mull) 1710, 1498, 1430, 1301, 1281,1275, 1204, 1174, 1164, 1115, 1094, and 1079 cm⁻¹. NMR (CDCl₃) 1.37 (t,J=7 Hz, 3, CH₃), 1.83 (m, 6, CH₂), 2.73 (m, 2, CH₂), 3.46 (m, 2, CH₂),4.31 (q, J=7 Hz, 3, CH₃), 7.95 (s, 1, CH).

PREPARATION 29

6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol(Formula G-5) Refer to Chart G.

A solution of6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-carboxylicacid ethyl ester (Formula G-4)(11.7 g) in THF (50 mL) was treated withLiAlH₄ (2.24 g) at 0° and reacted at ambient temperature for 1.5 hours.The reaction was quenched by serial additions of water and 15% sodiumhydroxide. The mixture was filtered and the filtrate was evaporated toyield crude6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol(Formula G-5). Crystallization of crude6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol(Formula G-5) from iso-propanol solution gave pure6,7,8,9-Tetrahydro-5H-cyclohept [d]imidazo[2,1-b]thiazole-3-methanol(Formula G-5) (7.7 g) m.p. 145-146°.

Anal. Calcd for C₁₁H₁₄N₂OS: C, 59.43; H, 6.35; N, 12.60; S, 14.24.Found: C, 59.43; H, 6.43; N, 12.78; S, 14.28. MS m/z 222 (M⁺), 205, 193,176, 164, 163, 151, 113 and 91. IR (mull) 3232, 3118, 3072, 1650, 1643,1631, 1613, 1554, 1546, 1361, 1355, 1337, 1318, 1295, 1779, 1243, 1143,1137, 1029, and 1025 cm⁻¹. NMR (CDCl₃) δ1.85 (m, 6, CH₂), 2.69 (m, 2,CH₂), 3.16 (m, 2, CH₂), 4.09 (b, 1, OH), 4.72 (s, 2, CH₂), 6.90 (s, 1,CH).

PREPARATION 30

6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-carboxaldehyde(Formula G-6) Refer to Chart G.

A solution of6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol(Formula G-5) (7.7 g) in DMF (50 mL) and toluene (220 mL) was treatedwith MnO₂ (14.3 g) and azeotropically distilled for 7 hours. The cooledmixture was filtered, the filtrate was concentrated to 50 mL, dilutedwith water and precipitated 6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-carboxaldehyde (Formula G-6)(6.89 g) wasfiltered. Crystallization from isopropanol solution gave pure6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazole[2,1-b]thiazole-3-carboxaldehyde (Formula G-6)(6.7 g), m.p.96-97°.

Anal. Calcd for C₁₁H₁₂N₂OS: C, 59.97; H, 5.49; N, 12.72; S, 14.56.Found: C, 59.96; H, 5.48; N, 12.77; S, 14.46. MS m/z 220 (M⁺), 205, 203,192, 191, 175, 174, 164, 163, 150 and 91. IR (mull) 3098, 1651, 1502,1445, 1396, 1344, 1312, 1272, and 1155 cm⁻¹. NMR (CDCl₃) δ1.75-2.0 (m,6, CH₂), 2.75 (m, 2, CH₂), 3.58 (m, 2, CH₂), 7.98 (s, 1, CH), 9.51 (s,1, CH).

EXAMPLE 15

6,7,8,9-Tetrahydro-α-(2-phenylethyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol(Formula G-7) Refer to Chart G.

A suspension of Mg (0.15 g) in ether (15 mL) was treated with(2-bromoethyl)benzene (0.91 mL) and reacted for 2.5 hours. This Grignardreagent was treated with 6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazole[2,1-b]thiazole-3-carboxaldehyde (Formula G-6) (0.44 g) andreacted for 24 hours. The supernate was decanted into 5% ammoniumchloride solution (100 mL) and the mixture was extracted with ethylacetate. Drying and evaporation of solvent gave a viscous residue (1.0g) which deposited pure6,7,8,9-Tetrahydro-α-(2-phenylethyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol (Formula G-7) (0.30 g), m.p.152-154° from isopropanol solution.

Anal. Calcd for C₁₉H₂₂N₂OS: C, 69.90; H, 6.79; N, 8.58; S, 9.82. Found:C, 69.59; H, 6.81; N, 8.39; S, 9.77. MS m/z 326 (M⁺), 309, 299, 282,222, 221, 205, 203, 178, 175, 165, 129, and 91. IR (mull) 3209, 3131,3091, 3066, 3028, 1611, 1606, 1436, 1360, 1342, 1332, 1313, 1274, 1161,1152, 1073, 1050, and 981 cm⁻¹. NMR (CDCl₃) δ1.79 (m, 6, CH₂), 2.26 (m,2, CH₂), 2.50 (b, 1, OH), 2.6-3.0 (m, 5, CH₂), 3.30 (m, 1, CH₂), 4.88(t, J=5 Hz, CH), 7.05 (s, 1, CH), 7.1-7.35 (m, 5, ArH).

EXAMPLE 16

6,7,8,9-Tetrahydro-α-(4-phenylbutyl)-5-H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol(Formula G-8) Refer to Chart G.

A suspension of Mg (0.15 g) in ether (15 mL) was treated with1-bromo-4-phenylbutane (1.4 g) and the Grignard reagent was generatedduring 2.5 hours. Solid 6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-carboxaldehyde (Formula G-6) (0.44 g) wasadded and reacted for 24 hours. The supernate was decanted into 5%ammonium chloride solution, product extracted into ethyl acetate, andthe extract was evaporated to an oil. The residue was triturated withhexane and pure 6,7,8,9-Tetrahydro-α-(4-phenylbutyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol (Formula G-8) (0.61 g) wasfiltered, m.p. 106° after recrystallization from acetonitrile solution.

Anal. Calcd for C₂₁H₂₆N₂OS: C, 71.15; H, 7.39; N, 7.90; S, 9.04. Found:C, 70.82; H, 7.40; N, 7.73; S, 9.12. MS m/z 354 (M⁺), 337, 336, 263,245, 221, 205, 203, 193, 168, 165, and 91. IR (mull) 3195, 3083, 3059,3021, 1611, 1604, 1496, 1434, 1367, 1353, 1330, 1314, 1305, 1272, 1231,1214, 1156, 1147, 1081, and 1062 cm⁻¹. NMR (CDCl₃) δ1.4-2.1 (m, 13, CH₂,OH), 2.6-2.75 (m, 4, CH₂), 3.05 (m, 1, CH₂), 3.32 (m, 1, CH₂), 4.87 (t,1, CH), 7.07 (s, 1, CH), 7.15-7.25 (m, 5, ArH).

PREPARATION 31

N′-(5,6,7,8,9,10-hexahydrocyclooctathiazolyl)-N,N-dimethylmethimidamide(Formula H-2) Refer to Chart H.

A solution of 2-aminocyclooctenothiazole (Formula H-1) (3.64 g) intoluene (20 mL) and DMF-dimethylacetal (5.3 mL) was heated at refluxtemperature for 1.5 hours. The cooled solution was diluted with toluene,treated with charcoal, filtered and evaporated to a crystalline residue.The residue was crystallized from hexane to yield pureN′-(5,6,7,8,9,10-hexahydrocyclooctathiazolyl)-N,N-dimethylmethimidamide(Formula H-2) (4.8 g), m.p. 53-56°.

Anal. Calcd for C₁₂H₁₉N₃S: C, 60.72; H, 8.07; N, 17.70; S, 13.51. Found:C, 60.69; H, 8.07; N, 17.76; S, 13.30. MS m/z 237 (M⁺), 222, 209, 194,182, 180, 115, and 98. IR (mull) 1622, 1618, 1549, 1494, 1433, 1413,1405, 1344, 1334, 1181, 1106, and 1097 cm⁻¹. NMR (CDCl₃) δ1.42 (m, 4,CH₂), 1.65 (m, 4, CH₂), 2.73 (m, 4, CH₂), 3.05 (s, 3, CH₃), 3.07 (s, 3,CH₃), 8.08 (s, 1, CH).

PREPARATION 32

2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6,7,8,9,10-hexahydrocyclooctathiazoliumbromide hydrate (Formula H-3) Refer to Chart H.

A solution ofN′-(5,6,7,8,9,10-hexahydrocyclooctathiazolyl)-N,N-dimethylmethimidamide(Formula H-2) (6.34 g) in ethyl bromoacetate (23 mL) was reacted at 25°for 96 hours. The suspension of thiazolium salt (Formula H-3) wasdiluted with ethyl acetate 250 mL and precipitated2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6,7,8,9,10-hexahydrocyclooctathiazoliumbromide hydrate (Formula H-3) (9.94 g) was filtered. An aliquotcrystallized from 2:1 ethyl acetate:acetonitrile analyzed as thehydrate, m.p. 96-99°.

Anal. Calcd for C₁₆H₂₆BrN₃O₂S·H₂O: C, 45.50; H, 6.68; Br, 18.92; N,9.95; S, 7.59. Found: C, 45.44; H, 6.66; Br, 18.80; N, 9.93; S, 7.61. MS(FAB) m/z 324 (M⁺−Br). IR (mull) 3457, 3410, 1751, 1650, 1612, 1523,1485, 1420, 1400, 1209, 1201, and 1130 cm⁻¹. NMR (CDCl₃) δ1.29 (t, 3,CH₃), 1.49 (m, 4, CH₂), 1.71 (m, 4, CH₂), 2.72 (t, J=6.2 Hz, 2, CH₂),2.78 (t, J=6.2 Hz, 2, CH₂), 3.17 (s, 3, CH₃), 3.63 (s, 3, CH₃), 4.83 (s,2, CH₂), 9.49 (s, 1, CH).

PREPARATION 33

5,6,7,8,9,10-Hexahydro-cyclooct[d]imidazo[2,1-b]thiazole-3-carboxylicacid ethyl ester (Formula H-4) Refer to Chart H.

A solution of2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6,7,8,9,10-hexahydrocyclooctathiazoliumbromide hydrate (Formula H-3) (9.6 g) in DMF (45 mL) was treated withDBU (5.3 mL) and reacted for 48 hours. The solution was diluted withcold water, acidified with 5% acetic acid solution, and precipitated5,6,7,8,9,10-Hexahydro-cyclooct[d]imidazo[2,1-b]thiazole-3-carboxylicacid ethyl ester (Formula H-4) (4.7 g) was filtered. The crude productwas fractionated on silica gel with 3:1 hexane:ethyl acetate to yieldpure5,6,7,8,9,10-hexahydrocyclooct[d]imidazo[2,1-b]thiazole-3-carboxylicacid ethyl ester (Formula H-4)(1.85 g), m.p. 79-81°, aftercrystallization from isopropanol solution.

Anal. Calcd for C₁₄H₁₈N₂O₂S: C, 60.41; H, 6.52; N, 10.06; S, 11.52.Found: C, 60.24; H, 6.44; N, 9.95; S, 11.37. MS m/z 278 (M⁺), 263, 250,233, 232, 231, 221, 199, 177, 107, and 105. IR (mull) 1718, 1505, 1431,1350, 1310, 1269, 1214, 1200, 1167, 1153, 1117, 1109, 1090, 1036, and1032 cm⁻¹. NMR (CDCl₃) δ1.35 (t, J=6 Hz, 3, CH₃), 1.54 (m, 2, CH₂),1.7-1.9 (m, 6, CH₂), 2.75 (t, J=6 Hz, 2, CH₂), 3.41 (t, J=6 Hz, 2, CH₂),4.30 (q, J=6 Hz, 2, CH₂), 7.97 (s, 1, CH).

PREPARATION 34

5,6,7,8,9,10-Hexahydrocyclooct[d]imidazo[2,1-b]thiazole-3-methanol (15d)(Formula H-5) Refer to Chart H.

A solution of5,6,7,8,9,10-Hexahydro-cyclooct[d]imidazo[2,1-b]thiazole-3-carboxylicacid ethyl ester (Formula H-4) (1.85 g) in THF (50 mL) was treated withLiAlH₄ (0.43 g) and reacted for 5 hours. The suspension was diluted to100 mL with THF and excess reagent was quenched with water then 15%sodium hydroxide. The mixture was filtered and the filtrate wasevaporated to yield pure5,6,7,8,9,10-Hexahydrocyclooct[d]imidazole[2,1-b]thiazole-3-methanol(Formula H-5) (1.44 g) which was used without further purification.

NMR (DMSO) δ1.40 (m, 4, CH₂), 1.6-1.75 (m, 4, CH₂), 2.77 (t, J=6 Hz, 2,CH₂), 3.10 (t, J=6 Hz, 2, CH₂), 4.58 (d, J=5 Hz, 2, CH₂), 5.32 (t, J=5Hz, 1, OH), 7.08 (s, 1, CH).

PREPARATION 35

5,6,7,8,9,10-Hexahydro-cyclooct[d]imidazo[2,1-b]thiazole-3-carboxaldehyde(Formula H-6) Refer to Chart H.

A solution of5,6,7,8,9,10-Hexahydrocyclooct[d]imidazo[2,1-b]thiazole-3-methanol(Formula H-5) (1.6 g) in hot toluene (250 mL) was treated with MnO₂ (3.8g) and azeotropically distilled for 1 hour. The cooled mixture wasfiltered and the combined filtrate and ethyl acetate washes wereevaporated to yield pure5,6,7,8,9,10-Hexahydro-cyclooct[d]imidazo[2,1-b]thiazole-3-carboxaldehyde(Formula H-6) (1.41 g), m.p. 106-107°, after crystallization fromhexane.

NMR (CDCl₃) δ1.40 (m, 4, CH₂), 1.55 (m, 4, CH₂), 2.80 (m, 2, CH₂), 3.42(m, 2, CH₂), 8.00 (s, 1, CH), 9.56 (s, 1, CH).

EXAMPLE 17

5,6,7,8,9,10-Hexahydro-α-(2-phenylethyl)cyclooct[d]imidazo-[2,1-b]thiazole-3-methanol(Formula H-7) Refer to Chart H.

Magnesium (0.29 g) in THF (70 mL) was treated with (2-bromoethyl)benzene (2.22 g) and the Grignard reagent was generated during 24 hours.Solid5,6,7,8,9,10-Hexahydro-cyclooct[d]imidazo[2,1-b]thiazole-3-carboxaldehyde(Formula H-6) (0.70 g) was added, reacted for 2.5 hours and thesupernate was decanted into 5% ammonium chloride solution. Theprecipitated5,6,7,8,9,10-Hexahydro-α-(2-phenylethyl)cyclooct[d]imidazo-[2,1-b]-thiazole-3-methanol(Formula H-7) was extracted into ethyl acetate, the extracts werewashed, dried, and evaporated to a viscous residue (1.51 g).Crystallization of the residue from acetonitrile solution provided pure5,6,7,8,9,10-Hexahydro-α-(2-phenylethyl)cyclooct[d]imidazo-[2,1-b]thiazole-3-methanol(Formula H-7) (0.79 g), m.p. 123-124°.

Anal. Calcd for C₂₀H₂₄N₂OS: C, 70.55; H, 7.10; N, 8.23; S, 9.42. Found:C, 70.36; H, 6.90; N, 8.18; S, 9.25. MS m/z 340 (M⁺), 323, 322, 313,296, 235, 219, 217, 236, 235, 219, 217, 207, 179, 165, 129, 105, and 91.IR (mull) 3378, 3210, 3103, 3080, 3061, 3047, 3023, 1647, 1613, 1603,1492, 1448, 1361, 1324, 1311, 1307, 1244, 1133, and 1041 cm⁻¹. NMR(CDCl₃) 1.2-1.9 (m, 8, CH₂), 2.20 (b, 1, OH), 2.25-2.40 (m, 2, CH₂),2.6-3.0 (m, 3, CH₂), 3.20 (m, 1, CH₂), 4.75 (t, J=5 Hz, 1, CH₂), 7.11(s, 1, CH), 7.17-7.34 (m, s, ArH).

PREPARATION 36

Imidazo[2,1-b]benzothiazole-3-methanol (Formula J-2) Refer to Chart J.

A solution of imidazo[2,1-b]benzothiazole-3-carboxylic acid ethyl ester(Formula J-1), (synthesized from 2-aminobenzothiazole by a modificationof the procedures described by Fajeli et al., Heterocycles, 1986, 24,379) (4.5 g) in THF (75 mL) was treated with LiAlH₄ (0.91 g) and reactedfor 5.25 hours. The suspension was quenched by serial additions of waterand 15% sodium hydroxide. The suspension was diluted with THF andfiltered. The filtrate was evaporated, the residue was triturated withhexane to yield imidazo[2,1-b]benzothiazole-3-methanol (Formula J-2)(2.77 g, 74%). Crude imidazo[2,1-b]benzothiazole-3-methanol (FormulaJ-2) was used without further purification.

NMR (CDCl₃) δ4.75 (s, 2, CH₂), 7.10 (s, 1, CH), 7.1-7.5 (m, 3, ArH), 7.7(m, 1, ArH).

PREPARATION 37

Imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula J-3) Refer toChart J.

A solution of imidazo[2,1-b]benzothiazole-3-methanol (Formula J-2) (2.0g) in DMF (30 mL) and toluene (200 mL) was treated with MnO₂ (4.5 g) andthe mixture was azeotropically distilled for 4.5 hours. A second changeof MnO₂ (2.0 g) and distillation for 1 hour completed the conversion.The suspension was filtered, the combined filtrate and ethyl acetatewashes of the cake were concentrated, the residue was diluted withwater, and filtered to yieldimidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula J-3) (2.0 g).Crude imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula J-3) wasused without further purification.

NMR (CDCl₃) δ7.1-7.5 (m, 3, ArH), 8.09 (s, 1, CH), 9.0 (d, J=9 Hz, 1,ArH), 9.74 (s, 1, CH).

EXAMPLE 18

α-(2-phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol (Formula J-4)Refer to Chart J.

Magnesium metal (0.29 g), 12 g atom) in dry THF (70 mL) was treated with(2-bromoethyl) benzene (0.44 mL) and an Iodine crystal. When the Iodinecolor had discharged additional (2-bromoethyl)benzene (1.2 mL) was addedand the suspension was reacted for 24 hours. Solidimidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula J-3) (0.606 g, 3.0mmol) was added and the mixture was reacted for 1.25 hours. The solutionwas decanted into 5% NH₄Cl solution (250 mL) and the mixture wasextracted with ethyl acetate. Drying and evaporation of the extract gavepure α-(2-phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol (FormulaJ-4) (0.81 g) after trituration of residue with acetonitrile. An aliquotof the triturated product was crystallized from acetonitrile solution toprovide an analytical sample ofα-(2-phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol (Formula J-4)(m.p. 174-175°).

Anal. Calcd for C₁₈H₁₆N₂OS. C, 70.10; H, 5.23; N, 9.08; S, 10.40. Found:C, 69.96; H, 5.39; N, 8.94; S, 10.46. MS 308 (M⁺), 291, 264, 217, 203,187, 175, 148, 134, and 77. IR (mull) 3237, 3157, 3136, 3123, 1602,1580, 1478, 1327, 1257, 1142, and 1041 cm⁻¹. NMR (DMSO) 2.2-2.4 (m, 2,CH₂), 2.7-2.9 (m, 2, CH₂), 5.07 (q, 1, CH), 5.25 (b, 1, OH), 7.15-7.45(m, 7, ArH, CH), 7.55 (m, 1, ArH), 7.70 (d, J=8 Hz, 1, ArH), 8.11 (d,J=8 Hz, 1, ArH).

PREPARATION 38

7-Methyl-imidazo[2,1-b]benzothiazole-3-methanol (Formula K-2) Refer toChart K.

A solution of 7-methylimidazo[2,1-b]benzothiazole-3-carboxylic acidethyl ester (synthesized from 2-amino-methylbenzothiazole according to amodification of the procedures described by Fajeli et al., heterocycles,1986, 24, 379) (2.69 g) in THF (25 mL) at 0° was treated with LiAlH₄(0.38 g) and reacted at 25° for 4.5 hours. Additional reagent (0.38 g)was required to complete the reduction. Excess reagent was quenched bysequential addition of water (4 mL) and 15% sodium hydroxide. Thecombined reaction filtrate and ethyl acetate washes were extracted withsaline solutions, dried, and evaporated. The residue deposited pure7-Methyl-imidazo[2,1-b]benzothiazole-3-methanol (Formula K-2) (1.43 g),m.p. 189-191°, from ethanol solution.

Anal. Calcd for C₁₁H₁₀N₂OS. C, 60.53; H, 4.62; N, 12.84; S, 14.69.Found: C, 60.22; H, 4.89; N, 12.66; S, 14.61. MS m/z 218 (M⁺), 217, 202,201, 189, 185, 160, 159, 148, 147, 121, and 77. IR (mull) 3202, 1632,1549, 1495, 1325, 1311, 1285, 1260, 1136, 1127, 1079, and 1035 cm⁻¹. NMR(DMSO) δ2.33 (s, 3, CH₃), 4.73 (s, 2, CH₂), 7.07 (s, 1, CH), 7.27 (d,J=9 Hz, 1, ArH), 7.67 (s, 1, ArH), 7.83 (d, J=9 Hz, 1, ArH).

PREPARATION 39

7-Methyl-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula K-3)Refer to Chart K.

A suspension of 7-Methyl-imidazo[2,1-b]benzothiazole-3-methanol (FormulaK-2) (0.82 g) in hot toluene (100 mL) was diluted with dioxane (10 mL)to effect dissolution of 7-Methyl-imidazo [2,1b]benzothiazole-3-methanol(Formula K-2). The solution was treated with activated MnO₂ (1.64 g) andazeotropically distilled for 1.25 hours. The suspension was filtered,the cake was washed with hot ethyl acetate, and the filtrate wasevaporated to a crystalline solid (0.69 g). Crystallization fromisopropanol gave pure7-Methyl-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula K-3)(0.56 g), m.p. 170-171°.

Anal. Calcd for C₁₁H₈N₂OS. C, 61.09; H, 3.73; N, 12.95; S, 14.83. Found:C, 61.01; H, 3.68; H, 12.91; S, 14.87. MS m/z 216 (M⁺), 201, 187, 162,160, 121, and 108. IR (mull) 1676, 1662, 1486, 1361, 1256, and 1159cm⁻¹. NMR (CDCl₃) δ2.49 (s, 3, CH₃), 7.33 (d, J=9 Hz, 1, ArH), 7.53 (s,1, ArH), 8.09 (s, 1, CH), 8.94 (d, J=9 Hz, 1, ArH), 9.74 (s, 1, CH).

EXAMPLE 19

7-Methyl-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol(Formula K-4) Refer to Chart K.

Magnesium (0.29 g, 12 g atom) in THF (60 mL) was treated with(2-bromoethyl)-benzene (1.64 mL) and reacted for 18 hours. Thesuspension was treated with solid 7-Methyl-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula K-3) (0.65 g) and reactedfor 2 hours. The reaction mixture was decanted into cold 5% ammoniumchloride solution and precipitated7-Methyl-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol(Formula K-4) (0.96 g) was filtered. An aliquot was crystallized frommethylene chloride/ethanol solution to yield pure7-Methyl-α-(2-phenylethyl) imidazo[2,1-b]benzothiazole-3-methanol(Formula K-4), m.p. 209-210°.

Anal. Calcd for C₁₉H₁₈N₂OS. C, 70.78; H, 5.63; N, 8.69; S, 9.94. Found:C, 70.68; H, 5.67; N, 8.59; S, 9.89. MS m/z 322 (M⁺), 295, 217, 201,189, 174, 162, 148, 130, and 65. IR (mull) 3362, 3295, 1544, 1489, 1458,1324, 1252, 1030, 1083, and 1039 cm⁻¹. NMR (DMSO) 2.25 (m, 2, CH₂), 2.45(s, 3, CH₃), 2.70-2.95 (m, 2, CH₂), 4.95 (q, 1, CH), 5.57 (d, 1, OH),7.13 (s, 1, CH), 7.22-7.30 (m, 6, ArH), 7.59 (s, 1, CH), 7.96 (d, J=8Hz, 1, ArH).

PREPARATION 40

7-Fluoro-imidazo[2,1-b]benzothiazole-3-methanol (Formula L-2) Refer toChart L.

A solution of 7-fluoroimidazo[2,1-b]benzothiazole-3-carboxylic acidethyl ester, (synthesized from 2-amino-methylbenzothiazole according toa modification of the procedures described by Fajeli et al.,Heterocycles, 1986, 24, 379) (1.93 g) in dry THF (50 mL) at 0° wastreated with LiAlH₄ (0.36 g) and reacted at 25° for one hour. Thesuspension was quenched by serial addition of water and 15% sodiumhydroxide. The suspension was filtered and the filtrate was evaporatedto yield crude 7-Fluoro-imidazo[2,1-b]benzothiazole-3-methanol (FormulaL-2) (1.59 g). Crystallization of crude7-Fluoro-imidazo[2,1-b]benzothiazole-3-methanol (Formula L-2) fromacetonitrile gave pure 7-Fluoro-imidazo[2,1-b]benzothiazole-3-methanol(Formula L-2) (1.3 g), m.p. 240-241°.

Anal. Calcd for C₁₀H₇FN₂OS. C, 54.04; H, 3.17; N, 12.60; S, 14.43.Found: C, 53.73; H, 3.18; N, 12.44; S, 14.05. MS m/z 222 (M⁺), 205, 193,178, 177, 166, 164, 162, 126, and 108. IR (mull) 3215, 3125, 3069, 1552,1492, 1281, 1212, 1202, and 1032 cm⁻¹. NMR (CDCl₃) δ5.00 (s, 1, CH),7.1-7.4 (m, 2, ArH, CH), 7.45 (m, 1, ArH), 8.00 (m, 1, ArH).

PREPARATION 41

7-Fluoro-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula L-3)Refer to Chart L.

A solution of 7-Fluoro-imidazo[2,1-b]benzothiazole-3-methanol (FormulaL-2) (1.0 g) in DMF (5 mL) was diluted with toluene (200 mL), the warmsolution was treated with activated MnO₂ (2.34 g) and azeotropicallydistilled for 4 hours. The cooled suspension ws filtered, the filtratewas concentrated in vacuo and the residue was diluted with ice water.Precipitated 7-Fluoro-imidazo [2,1-b]benzothiazole-3-carboxaldehyde(Formula L-3) was filtered and recrystallized from acetonitrile to yieldpure 7-Fluoro-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula L-3)(0.89 g), m.p. 182-183°.

Anal. Calcd for C₁₀H₅FN₂OS. C, 54.54; H, 2.29; N, 12.72; S, 14.56.Found: C, 54.33; H, 2.32; N, 12.70; S, 14.11. MS m/z 220 (M⁺), 219, 192,191, 164, 110, and 108. IR (mull) 3306, 3119, 3100, 3082, 1678, 1664,1582, 1518, 1482, 1441, 1312, 1264, 1250, 1199, 1161 and 889 cm⁻¹. NMR(CDCl₃) δ7.26 (m, 1, ArH), 7.46 (q, 1, ArH), 8.12 (s, 1, CH), 9.12 (q,1, ArH), 9.75 (s, 1, CH).

EXAMPLE 20

7-Fluoro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol(Formula L-4) Refer to Chart L.

Magnesium (0.146 g) in anhydrous ether (15 mL) was treated with(2-bromoethyl)-benzene (0.82 mL) and reacted for 2.5 hours. The Grignardreagent was treated with solid 7-Fluoro-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula L-3) (0.44 g). Incompleteconversion was observed, an additional charge of Grignard reagent wasadded, and reacted for 24 hours. The reaction mixture was decanted into5% ammonium chloride solution and extracted with ethyl acetate. Theextract was washed, dried, and evaporated to a solid residue (0.60 g) ofcrude 7-Fluoro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol(Formula L-4). Crystallization from isopropanol solution gave pure7-Fluoro-α-(2-phenylethyl) imidazo[2,1-b]benzothiazole-3-methanol(Formula L-4), m.p. 195-196°. Anal. Calcd for C ₁₈H₁₅FN₂OS. C, 66.24; H,4.63; N, 8.58; S, 9.82. Found: C, 66.08; H, 4.64; N, 8.48; S, 9.72. MSm/z 326 (M⁺), 235, 221, 205, 193, 179, 193, 179, 166, 152, and 91. IR(mull). 3301, 1547, 1486, 1321, 1260, 1208, 1200, 1133, and 1039 cm⁻¹.NMR (CDCl₃/CD₃OD) δ2.33 (q, J=7.6 Hz, 2, CH₂), 2.76-3.0 (m, 2, CH₂),5.00 (t, J=7.6 Hz, 1, CH), 7.1-7.4 (m, 9, ArH, CH), 8.01 (m, 1, ArH).

PREPARATION 42

7-Methoxy-imidazo[2,1-b]benzothiazole-3-methanol (Formula M-2) Refer toChart M.

A solution of 7-methoxy-imidazo[2,1-b]benzothiazole-3-carboxylic acidethyl ester (5.5 g) in THF (150 mL) at 0° was treated with LiAlH₄ (1.03g) and reacted for 1 hour. The reaction was quenched by serial additionof water and 15% sodium hydroxide. The suspension was filtered, thecombined filtrate and THF washes were evaporated to yield7-Methoxy-imidazo [2,1-b]benzothiazole-3-methanol (Formula M-2) (3.9 g).Crystallization from acetonitrile solution gave7-Methoxy-imidazo[2,1-b]benzothiazole-3-methanol (Formula M-2), m.p.202-204°.

Anal. Calcd for C₁₁H₁₀N₂O₂S. C, 56.39; H, 4.30; N, 11.96; S, 13.69.Found: C,56.27; H, 4.35; N, 11.88; S, 13.37. MS m/z 234 (M⁺) 217, 202,192, 190, and 174. IR (mull) 3178, 3067, 3037, 3005, 1613, 1584, 1550,1495, 1316, 1289, 1233, 1132, 1075, 1048, and 1032 cm⁻¹. NMR (CDCl₃)δ3.87 (s, 3, CH₃), 4.96 (d, 2, CH₂), 7.10 (q, J=2.5, 9 Hz, 1, ArH), 7.18(m, 2, ArH, CH), 7.92 (d, J=9 Hz, 1, ArH).

PREPARATION 43

7-Methoxy-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula M-3)Refer to Chart M.

A solution of 7-Methoxy-imidazo[2,1-b]benzothiazole-3-methanol (FormulaM-2) (4.0 g) in DMF (25 mL) was diluted with toluene (200 mL) and thewarm solution was treated with MnO₂ (8.84 g). The suspension wasazeotropically distilled for 4 hours, cooled to 50°, and filtered. Thecombined filtrate and toluene washes were concentrated and theconcentrate was diluted with water. Precipitated7-Methoxy-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula M-3)(3.8 g) was filtered and recrystallized from acetonitrile to yield pure7-Methoxy-imidazo [2,1-b]benzothiazole-3-carboxaldehyde (Formula M-3)(3.79 g), m.p. 168-169°.

Anal. Calcd for C₁₁H₈N₂O₂S. C, 56.88; H, 3.47; N, 12.06; S, 13.81.Found: C, 56.87; H, 3.49; N, 12.00; S, 13.81. MS m/z 232 (M⁺), 217, 204,203, 189, 176, 161, 150, 146, 144, 134, 116. IR (mull) 3111, 3086, 3062,3011, 1670, 1602, 1515, 1491, 1448, 1356, 1313, 1272, 1231, 1165, and1029 cm⁻¹. NMR (CDCl₃) δ3.90 (s, 3, CH₃), 7.08 (q, J=2.5, 9 Hz, 1, ArH),7.21 (d, J=2.5 Hz, 1, ArH0, 8.98 (d, J=9 Hz, 1, ArH).

EXAMPLE 21

7-Methoxy-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol(Formula M-4) Refer to Chart M.

Magnesium (0.146 g) in anhydrous ether (15 mL) was treated with(2-bromoethyl)benzene (0.82 mL) and reacted for 2.5 hours. Solid7-Methoxy-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula M-3)(0.46 g) was added and reacted for 24 hours. The reaction mixture wasquenched with 5% ammonium chloride solution and product was extractedinto ethyl acetate. Drying and evaporation of solvent gave crude7-Methoxy-α-(2-phenylethyl) imidazo[2,1-b]benzothiazole-3-methanol(Formula M-4) which was recrystallized from acetonitrile solution toprovide pure7-Methoxy-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol(Formula M-4) (0.60 g), m.p. 166-167°.

Anal. Calcd for C₁₉H₁₈N₂O₂S. C, 67.43; H, 5.36; N, 8.28; S, 9.48. Found:C, 67.20; H, 5.43; N, 8.15; S, 9.31. MS m/z 338 (M⁺), 311, 294, 247,246, 233, 218, 217, 205, 190, 162, 147, 146, and 91. IR (mull) 3270,1610, 1002, 1584, 1543, 1488, 1313, 1286, 1231, 1220, 1069, 1043, 1036and 866 cm⁻¹. NMR (CDCl₃) δ2.32 (q, J=7.4 Hz, 2, CH₂), 2.59 (d, 1, OH),2.81-2.94 (m, 2, CH₂), 3.85 (s, 1, CH₃), 5.01 (m, 1, CH), 6.94 (q,J=2.5, 9 Hz, 1, ArH), 7.09 (d, J=9 Hz, 1, ArH), 7.13 (s, 1, CH),7.20-7.34 (m, 4, ArH), 7.89 (d, J=9 Hz, 1, ArH).

PREPARATION 44

2-[[(Dimethylamino)methylene]amino]-5,6,7,8-tetrahydro-3-(2-oxopropyl)-4H-cycloheptathiazoliumchloride dihydrate (Formula N-3). Refer to Chart N.

A solution ofN′-(5,6,7,8-tetrahydro-4H-cycloheptathiazol)-N,N-dimethylmethimidamide(Formula N-2), 1.12 g, in chloroacetone (10 mL) was reacted for 48hours. The solution was evaporated in vacuo and the residue wasevaporated from toluene. The residual oil crystallized in contact withether and the pure 2-[[(dimethylamino)methylene]amino]-5,6,7,8-tetrahydro-3-(2-oxopropyl)-4H-cycloheptathiazoliumchloride was obtained as a dihydrate (1.49 g), m.p. 59°0 (Formula N-3).

Anal. Calcd. for C₁₄H₂₂ClN₃OS. C, 47.79; H, 7.45; Cl, 10.08; N, 11.94;S, 9.11. Found: C, 46.90; H, 7.52; Cl, 9.62; S, 8.91. MS m/z 280(M⁺−Cl⁻). IR (mull) 3425, 3377, 1731, 1647, 1517, 1479, 1447, 1435,1406, and 1365 cm⁻¹. NMR (CDCl₃) δ1.81 (m, 6, CH₂), 2.40 (S, 3, CH₃),2.62 (m, 2, CH₂), 2.71 (m, 2, CH₂), 3.18 (S, 3, CH₃), 3.51 (S, 3, CH₃),5.36 (S, 2, CH_(2l ),) 8.01 (S, 1, CH).

PREPARATION 45

1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl ethanone(Formula N-4). Refer to Chart N.

To a solution of2-[[(dimethylamino)methylene]amino]-5,6,7,8-tetrahydro-3-(2-oxopropyl)-4H-cycloheptathizoliumchloride dihydrate (Formula N-3), 1.0 g, in dimethyl-formamide (5.0 ml),1,8-diazabicyclo[5,4,0]undec-7-ene (0.9 ml) was added. The solution wasreacted for 24 hours, diluted with ice-water and precipitated productwas filtered. Crystallization of the dried precipitate (0.502 g) fromether-hexane solution gave pure 1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl ethanone (0.35 g), m.p. 80-82° (FormulaN-4).

Anal. Calcd for C₁₂H₁₄N₂OS: C, 61.51; H, 6.02; N, 11.86; S, 13.69.Found: C, 61.31; H, 6.01; N, 11.91; S, 13.46. MS m/z 234 (M⁺), 219, 206,196, 177, 91, 77, 65, and 43. IR (mull) 1655, 1442, 1424, 1346, 1307,1269, 1209, and 1191 cm⁻¹.

PREPARATION 46

3-(3-Fluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=3-fluoro). Refer to Chart N.

[1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-yl)-ethanone(Formula N-4), 2.34 g and 3-fluorobenzaldehyde were reacted usingnon-critical variations of the teachings Example 15 to give3-(3-fluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula N-5,X=3-fluoro), 3.08 g, m.p. 176-177°.

Anal. Calcd for C₁₉H₁₇FN₂OS. C, 67.04; H, 5.03; N, 8.23; S, 9.42. Found:C, 67.05; H, 5.04; N, 8.14; S, 9.26. MS m/z 340 (M⁺), 323, 311, 297,283, 245, 231, 217, 203, 190, and 121. IR (mull) 1654, 1600, 1505, 1421,1359, 1307, 1268, 1197, 1034, and 960 cm⁻¹. NMR (CDCl₃) δ1.84 (m, 6,CH₂), 2.79 (m, 2, CH₂), 3.48 (m, 1, CH₂), 7.12 (m, 1, ArH), 7.22-7.55(m, 4, ArH), 7.75 (d, J=16 Hz, 1, CH), 8.12 (S, 1, CH).

EXAMPLE 22

α-[2-(3-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-imidazo[2,1-b]thiazole-3-methanol(Formula N-8, X=3-fluoro). Refer to Chart N.

3-(3-Fluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=3-fluoro), 0.34 g, in ethanol (35 mL) was treated withNaBH₄ (0.11 g), reacted for 3 hours, and solvent removed in vacuo. Theresidue was suspended in water, filtered and the filter cake wascrystallized from acetonitrile to provide pure α-[2-(3-fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H, imidazo[2,1-b]thiazole-3-methanol, 0.30g, m.p. 175-176° (Formula N-8, X=3-fluoro).

Anal. Calcd for C₁₉H₁₉FN₂OS. C, 66.64; H, 5.59; N, 8.18; S, 9.36. Found:C, 66.49; H, 5.58; N, 8.16; S, 9.36. MS m/z 342 (M⁺), 325, 313, 298,247, 233, 221, 205, 192, and 175. IR (mull) 3126, 3114, 1584, 1445,1440, 1146, 1140, and 1096 cm⁻¹. NMR (CDCl₃) δ1.80 (m, 6, CH₂), 2.70 (m,2,CH₂), 3.10 (m, 1, CH₂), 3.35 (m, 1, CH₂), 5.70 (m, 1, CH), 6.55 (q,J=4 Hz, J=15 Hz, 1, CH), 6.72 (d, J=15 Hz, 1, CH), 6.85 (m, 5, ArH, CH).

EXAMPLE 23

α-[2-(3-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula N-7, X=3-fluoro). Refer to Chart N.

A suspension of3-(3-fluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-6, X=3-fluoro), 1.02 g, in THF (100 mL) at −78° was treatedwith LiAlH₄ (0.27 g) and reacted for 18 hours. The mixture was thenmaintained at −20° for 24 hours and excess reagent was quenched. Themixture was filtered, the filtrate was concentrated, the residue wasdissolved in ethyl acetate, washed with saline, dried and evaporated.The residue (0.30 g) was crystallized from acetonitrile to yield pureα-[2-(3-fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,0.21 g (m.p. 141-144°), Formula N-7, X=3-fluoro.

Anal. Calcd for C₁₉H₂₁FN₂OS. C, 66.25; H, 6.15; N, 8.03; S, 9.19. Found:C, 65.58; H, 6.09; N, 8.03; S, 9.19. MS m/z 344 (M⁺), 317, 221, 203,193, 175, and 165. IR (mull) 3184, 3136, 3059, 3043, 1614, 1589, 1492,1273 and 1074 cm⁻¹. NMR (CDCl₃) δ1.82 (m, 6, CH₂), 2.25 (m, 2, CH₂),2.60-3.05 (m, 5, CH₂), 3.28 (m, 1, CH₂), 4.87 (t, 1, CH), 6.80-7.40 (m,5, ArH, CH).

PREPARATION 47

6,7,8,9-Tetrahydro-[2-(4-fluorophenyl)-E-ethenyl]-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-ylmethanone (Formula N-5, X=4-fluoro).

This compound was prepared as in EXAMPLE 15 by condensation of1-(6,7,8,9-tetrahydro-5H-cyclohept [d]imidazo[2,1-b]thiazol-3-ylethanone (Formula N-4) with 4-fluorobenzaldehyde to provide6,7,8,9-Tetrahydro-[2-(4-fluorophenyl)-E-ethenyl]-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl methanone (Formula N-5, X=4-fluoro), 3.1g, m.p. 187-188°.

Anal. Calcd for C₁₉H₁₇FN₂OS. C, 67.04; H, 5.03; N, 8.23; S, 9.42. Found:C, 66.74; H, 5.12; N, 8.01; S, 9.17. MS m/z 340 (M⁺), 323, 311, 297,283, 245, 231, 218, 203, 190, and 175. IR (mull) 1653, 1597, 1589, 1507,1421, 1361, 1204, 1193, 1158, and 832 cm⁻¹. NMR (CDCl₃) δ1.84 (m, 6,CH₂), 2.76 (m, 2, CH₂), 2.44 (m, 2, CH₂), 7.05-7.30 (m, 3, ArH, CH),7.60 (m, 2, ArH), 7.73 (d, J=16 Hz, 1, CH), 8.10 (S, 1, CH).

EXAMPLE 24

α-[2-(4-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula N-7, X=4-fluoro). Refer to Chart N.

3-(4-Fluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl-2-propene-1-one,Formula N-5, X=4-fluoro, 1.02 g, was reduced by non-critical variationsof EXAMPLE 23 to give pureα-[2-(4-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol (Formula N-7, X=4-fluoro), m.p.144-146°.

Anal. Calcd for C₁₉H₂₁FN₂OS. C, 66.25; H, 6.15; N, 8.13; S, 9.31. Found:C, 65.99; H, 6.17; N, 8.02; S, 9.22. MS m/z 344 (M⁺), 327, 317, 221,205, 193, 165 and 129. IR (mull) 3197, 3133, 1513, 1438, 1234, 1223,1158 and 1074 cm⁻¹. NMR (CDCl₃) δ1.85 (m, 6, CH₂), 2.25 (m, 2, CH₂),2.60-3.05 (m, 5, CH₂), 3.25 (m, 1, CH₂), 4.75 (t, 1, CH), 6.95-7.22 (m,5, ArH, CH).

EXAMPLE 25

α-[2-(4-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula N-8, X=4-fluoro). Refer to Chart N.

3-(4-Fluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=4-fluoro), was reduced toα-[2-(4-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol, m.p. 175-176° (Formula N-8,X=4-fluoro) by non-critical variations of EXAMPLE 22.

Anal. Calcd for C₁₉H₁₉FN₂OS. C, 66.64; H, 5.59; N, 8.18; S, 9.36. Found:C, 66.49; H, 5.58; N, 8.16; S, 9.36. MS m/z 342 (M⁺), 325, 313, 298,247, 233, 221, 205, 192, and 175. IR (mull) 3126, 3114, 1584, 1445,1440, 1146, 1140, and 1096 cm⁻¹. NMR (CDCl₃) δ1.80 (m, 6, CH₂),2.60-2.75 (m, 3, CH₂, OH), 3.10 (m, 1, CH), 3.35 (m, 1, CH), 5.70 (b-,1, CH), 6.45 (q, J=4, J=15 Hz, 1, CH), 6.70 (d, J=15 Hz, 1, CH), 7.04(m, 2, ArH), 7.40 (m, 2, ArH).

PREPARATION 48

3-(3-Bromophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=3-bromo). Refer to Chart N.

1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)ethanone(Formula N-4), and 4-bromobenzaldehyde (1.62 g) were condensed toprovide3-(3-Bromophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=3-bromo), 1.2 g, m.p. 125-126°, after crystallizationfrom isopropanol.

Anal. Calcd for C₁₉H₁₇BrN₂SO. C, 56.86; H, 4.27; Br, 19.91; N, 6.98; S,7.99. Found: C, 56.72; H, 4.33; Br, 19.82; N, 6.84; S, 7.97. MS m/z 442,440 (M⁺), 245, 231, 102. IR (mull) 3105, 3078, 3060, 1652, 1597, 1421,1420, 1365, 1305, and 1195 cm⁻¹. NMR (CDCl₃) 1.84 (m, 6, CH₂), 2.76 (m,2, CH₂), 3.44 (m, 2, CH₂), 7.31 (m, 2, ArH, CH), 7.52 (m, 2, ArH), 7.72(m, 2, ArH), 6.12 (S, 1, CH).

PREPARATION 49

3-93-Bromophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula N-6, X=3-Bromo). Refer to Chart N.

A suspensionof Te (1.28 g) in N₂-degassed ethanol (20 mL) was treatedwith NaBH₄ (0.83 g) and heated at reflux temperatures for 30 minutes.The mixture was treated with acetic acid (1.2 mL) in ethanol (5 mL)dropwise at −10 to −20°. The mixture was warmed to 25°, treated withsolid3-(3-bromophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(0.40 g, Formula N-5, X=3-bromo) and reacted for 2.5 hours. Air waspassed through the mixture, the precipitated inorganic material wasfiltered, and the filtrate was evaporated to a crystalline residue.Crystallization of the residue from isopropanol gave pure3-(3-Bromophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone (Formula N-6, X=3-Bromo),m.p. 77-79°.

Anal. Calcd for C₁₉H₁₉BrN₂OS. C, 56.58; H, 4.75; Br, 19.81; N, 6.95; S,7.95. Found: C, 56.39; H, 4.66; Br, 19.60; N, 6.79; S, 7.93. MS m/z 404,402 (M⁺), 375, 247, 233, 219, and 192. IR (mull) 3122, 3061, 3048, 3010,1653, 1502, 1475, 1424, 1307, 1273, and 1196 cm⁻¹. NMR (CDCl₃) δ1.82 (m,6, CH₂), 2.75 (m, 2, CH₂), 3.03 (m, 2, CH₂), 3.15 (m, 2, CH₂), 3.40 (m,2, CH₂), 7.17 (m, 2, ArH), 7.30-7.40 (m, 2, ArH), 7.97 (S, 1, CH).

EXAMPLE 26

α-[2-(3-Bromophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-[2,1-b]thiazol-3-methanol(Formula N-7). Refer to Chart N.

3-(3-Bromophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone,0.10 g, (Formula N-6, X=3-bromo) was reduced by non-critical variationsof EXAMPLE 12 to provideα-[2-(3-Bromophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol (Formula N-7), 0.07 g, m.p.137-141°.

Anal. Calcd for C₁₉H₂₁BrN₂OS. C, 56.30; H, 5.22; Br, 19.71; N, 6.91.Found: C, 56.02; H, 5.24; Br, 19.49; N, 6.78.

MS m/z 406, 404 (M⁺), 379, 377, 362, 360, 221, 205, 203, and 193.

IR (mull) 3064, 1608, 1594, 1567, 1445, 1434, 1424, 1365, 1325, 1276,1150, and 1070 cm⁻¹.

NMR (CDCl₃) 1.80 (m, 6, CH₂), 2.22 (m, 2, CH₂), 2.60-3.05 (m, 5, CH₂),3.27 (m, 1, CH₂), 4.85 (m, 1, CH), 7.0-7.5 (m, 5, ArH, CH).

PREPARATION 50

6,7,8,9-Tetrahydro-[2-(3-chlorophenyl)-ethenyl-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl methanone (Formula N-5, X=3-chloro). Refer to ChartN.

1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-ylethanone (Formula N-4), 1.87 g, and 3-chlorobenzaldehyde (0.216 g) werecondensed following non-critical variations of Example 15 to provide6,7,8,9-Tetrahydro-[2-(3-chlorophenyl)-ethenyl-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-ylmethanone (Formula N-5, X=3-chloro), (2.72 g), m.p. 137-139°.

Anal. Calcd for C₁₉H₁₇CIN₂OS. C, 63.95; H, 4.80; Cl, 9.94; S, 8.99.Found: C, 63.93; H, 4.89; Cl, 9.80; N, 7.94; S, 8.97.

MS m/z 358, 356 (M⁺), 341, 339, 327, 245, 231, 217, and 203.

IR (mull) 1654, 1601, 1494, 1422, 1364, 1190, 1046, 968, 962, and 788cm⁻¹.

NMR (CDCl₃) 1.85 (m, 6, CH₂), 2.79 (m, 2, CH₂), 3.48 (m, 2, CH₂),7.25-7.52 (m, 4, CH, ArH), 7.60 (S, 1, ArH), 7.70 (d, J=16 Hz, 1, CH),8.12 (S, 1, CH).

PREPARATION 51

3-(3-Chlorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone (Formula N-6, X=3-chloro). Refer to Chart N.

3-(3-Chlorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=3-chloro) (0.36 g) was reduced by non-criticalvariations of PREPARATION 49 to yield3-(3-chlorophenyl)-1-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(0.30 g), (Formula N-6, X=3-chloro).

MS m/z 360, 358 (M⁺), 247, 233, 219, 205, 192, 177, 165, 127 and 125.

NMR (CDCl₃) δ 1.82 (m, 2, CH₂), 2.75 (m, 2, CH₂), 3.0-3.2 (m, 4, CH₂),3.41 (m, 2, CH₂), 7.05-7.30 (m, 4, ArH), 7.97 (S, 1, CH).

EXAMPLE 27

α-[2-(3-Chlorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula N-7, X=3-chloro). Refer to Chart N.

3-(3-Chlorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula N-6, X=3-chloro) was reduced accoring to EXAMPLE 12 to provideα-[2-(3-Chlorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula N-7, X=3-chloro).

Anal. Calcd for C₁₉H₂₁CIN₂OS. C, 63.23; H, 5.86; Cl, 9.82; N, 7.76; S,8.88. Found: C, 63.21; H, 5.96; Cl, 9.55; N, 7.72; S, 8.86.

MS m/z 362, 360 (M⁺), 344, 342, 335, 333, 316, 231, 221, 205, and 91.

IR (mull) 3171, 3115, 3071, 3043, 1437, 1428, 1153, 1078, 795, and 784cm⁻¹.

NMR (CDCl₃) δ 1.80 (m, 6, CH₂), 2.23 (m, 2, CH₂), 2.65-3.10 (m, 6, CH₂),3.28 (m, 1, CH₂), 4.84 (t, 1, CH), 6.98 (s, 1, CH), 7.05-7.42 (m, 4,ArH).

PREPARATION 52

3-(3,5-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=3,5-difluoro). Refer to Chart N.

1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-ethanone(Formula N-4, 1.8 g in THF (50 mL) was condensed with3,5-difluorobenzaldehyde according to non-critical variations inPREPARATION 15 to yield pure3-(3,5-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=3,5-difluoro), 0.51 g, m.p. 207-209°.

Anal. Calcd for C₁₉H₁₆F₂N₂OS. C, 63.67; H, 4.50; N, 7.82; S, 8.95.Found: C, 63.32; H, 4.47; N, 7.72; S, 8.80.

MS m/z 358 (M⁺), 339, 330, 301, 245, 231, 217, 203, 190, 167, and 139.

IR (mull) 1655, 1620, 1600, 1450, 1419, 1364, 1305, 1197, 1124, and 847cm⁻¹.

NMR (CDCl₃) δ 1.84 (m, 6, CH₂), 2.76 (m, 2, CH₂), 3.44 (m, 2, CH₂), 6.86(m, 1, ArH), 7.11 (m, 2, ArH), 7.30 (d, J=19 Hz, 1, CH), 7.67 (d, J=19Hz, 1, CH), 8.15 (s, 1, CH).

PREPARATION 53

3-(3,5-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula N-6, X=3,5-difluoro). Refer to Chart N.

3-(3,5-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=3,5-difluoro) (0.25 g) was reduced with NaHTe to3-(3,5-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(0.15 g), (Formula N-6, X=3,5-difluoro), m.p. 112-114°, according tonon-critical variation of PREPARATION 49.

MS m/z 360 (M⁺), 317, 247, 219, 193, 192 and 127.

NMR (CDCl₃) δ 1.81 (m, 6, CH₂), 2.73 (m, 2, CH₂), 3.05 (m, 2, CH₂), 3.13(m, 2, CH₂), 3.43 (m, 2, CH₂), 6.45 (m, 1, ArH), 6.76 (m, 2, ArH), 7.99(S, 1, CH).

EXAMPLE 28

α-[2-(3,5-Difluorophenyl)ethyl]-1-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazothiazol-3-methanol(Formula N-7, X=3,5-difluoro). Refer to Chart N.

3-((3,5-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula N-6, X=3,5-difluoro), 0.10 g, was reduced with NaBH₄ accordingto non-critical variations of EXAMPLE 12 to yieldα-[2-(3,5-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazothiazol-3-methanol(Formula N-7, X=3,5-difluoro), 0.09 g, m.p. 165-166°.

Anal. Calcd for C₁₉H₂₀F₂N₂OS. C, 62.96; H, 5.56; N, 7.73; S, 8.85.Found: C, 63.22; H, 5.51; N, 7.80; S, 8.79.

MS m/z 362 (M⁺), 344, 335, 318, 231, 221, 193, 165, and 91.

IR (mull) 3186, 3135, 1625, 1595, 1432, 1318, 1314, 1112, 986 and 965cm⁻¹.

NMR (CDCl₃) δ 1.82 (m, 6, CH₂), 2.25 (M, 2, CH₂), 2.65-3.05 (m, 5, CH₂),3.30 (m, 1, CH), 4.85 (m, 1, CH), 6.6-6.8 (m, 3, ArH), 7.10 (S, 1, CH).

PREPARATION 54

6,7,8,9-Tetrahydro-[2-(4-dimethylaminophenyl)-E-ethenyl]-4H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl-methanone(Formula N-5, X=4-dimethylamino).

1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl ethanone(Formula N-4), 3.51 g, and 4-dimethylaminobenzaldehyde (4.48 g) werecondensed according to non-critical variations of PREPARATION 15 toyield pure6,7,8,9-Tetrahydro-[2-(4-dimethylaminophenyl)-E-ethenyl]-4H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl-methanone(3.78 g), m.p. 214-215°.

Anal. Calcd for C₂₁H₂₃N₃OS. C, 69.01; H, 6.34; N, 11.50; S, 8.77. Found:C, 68.75; H, 6.46; N, 11.43; S, 8.65.

MS m/z 365 (M⁺), 350, 231, 218, 190, 174, 146, and 134.

IR (mull) 1645, 1610, 1573, 1524, 1506, 1422, 1360, 1182, 1171, and 815cm⁻¹.

NMR (CDCl₃) δ 1.85 (m, 6, CH₂), 2.77 (m, 2, CH₂), 3.05 (S, 6, CH₃), 3.44(m, 2, CH₂), 6.71 (d, J=9 Hz, 2, ArH), 7.10 (d, J=16 Hz, 1, CH), 7.51(d, J=9 Hz, 2, ArH, 7.75 (d, J=16 Hz, 1, CH), 8.03 (S, 1, CH).

EXAMPLE 29

α-[2-(4-dimethylaminophenyl)ethyl-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazo-[2,1-b]thiazol-3-methanol(Formula N-7, X=4-dimethylamino). Refer to Chart N.

3-(4-Dimethylaminophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=4-dimethylamino), was reduced according to non-criticalvariations of EXAMPLE 23 to provideα-[2-(4-dimethylaminophenyl)ethyl-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula N-7, X=4-dimethylamino), 0.15 g, m.p. 168-170°, afterchromatographic purification.

Anal. Calcd for C₂₁H₂₇N₃OS. C, 68.26; H, 7.36; N, 11.37; S, 8.68. Found:C, 68.08; H, 7.34; N, 11.33; S, 8.61.

MS m/z 369 (M⁺), 354, 235, 221, 193, 177, 163, 148 and 134.

IR (mull) 3149, 3118, 3099, 1616, 1522, 1446, 1347, 1150, and 1052 cm⁻¹.

NMR (CDCl₃) δ 1.73-2.02 (m, 6, CH), 2.26 (m, 2, CH₂), 2.6-2.85 (m, 5,CH₂), 2.92 (S, 6, CH₃), 3.30 (m, 1, CH), 4.90 (b, 1, CH), 6.70 (d, J=9Hz, 2, ArH), 7.08 (d, J=9 Hz, 2, ArH), 7.11 (S, 1, CH).

EXAMPLE 30

α-[2-(4-Dimethylaminophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-methanol(Formula N-8, X=4-dimethylamino). Refer to Chart N.

3-(4-Dimethylaminophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=4-dimethylamino) 0.37 g, was reduced according tonon-critical variations of EXAMPLE 22 to provideα-[2-(4-Dimethylaminophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(0.20 g), m.p. 168-170° (Formula N-8, X=4-dimethylamino).

Anal. Calcd for C₂₁H₂₅N₃OS. C, 68.63; H, 6.86; N, 11.43; S, 8.73. Found:C, 68.38; H, 6.80; N, 11.34; S, 8.59.

MS m/z 367 (M⁺), 350, 338, 220, 205, 175, 158, 149, and 147.

IR (mull) 3133, 3119, 1612, 1522, 1444, 1349, 1145, and 1096 cm⁻¹.

NMR (CDCl₃) δ 1.79 (m, 6, CH₂), 2.60 (b, 1, OH), 2.69 (m, 2, CH₂), 2.97(s, 6, CH₃), 3.10 (m, 1, CH₂), 3.37 (m, 1, CH₂), 5.67 (t, 1, CH), 6.35(q, 1, CH), 6.60 (d, 1, CH), 6.68 (d, J=9 Hz, 2, ArH), 7.10 (S, 1, CH),7.30 (d, J=9 Hz, 2, ArH).

PREPARATION 55

(E)-N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxo-1-propenyl]phenyl-4-methylbenzenesulfonamide(Formula N′-2, X=3-toluenesulfonamide). Refer to Chart N′.

1-(2,3-Dimethylimidazo[2,1-b]-thiazol-5-yl ethanone (Formula N′-1), 0.97g, was condensed with the 3-toluensulfonamide of benzaldehyde, m.p.126-127°, prepared from toluene sulfonyl chloride and3-aminobenzaldehyde, according to non-critical modifications ofPREPARATION 15 to provide pure(E)-N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxo-1-propenyl]phenyl-4-methylbenzenesulfonamide,m.p. 236-237°, Formula N′-2.

Anal. Calcd for C₂₃H₂₁N₃O₃S₂. C, 61.17; H, 4.69; N, 9.30; S, 14.20.Found: C, 60.91; H, 4.75; N, 9.25; S, 14.09.

MS mz 451 (M⁺), 422, 296, 268, 205, 191, 179, 177, 168, 106, and 91.

IR (mull) 3145, 3101, 3083, 3025, 3012, 1668, 1618, 1603, 1586, 1520,1433, 1365, 1340, 1311, 1306, 1291, 1270, 1212, and 1159 cm⁻¹.

NMR (CDCl₃) δ 2.38 (S, 6, CH₃), 2.67 (S, 3, CH₃), 7.1-7.4 (m, 8, ArH,CH), 7.6-7.7 (m, 3, ArH, CH).

PREPARATION 56

N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxopropyl]phenyl]-4-methyl-benzenefulfonamide(Formula N′-3, X=3-toluenesulfonamide). Refer to Chart N′.

(E)-N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxo-1-propenyl]phenyl]4-methylbenzenesulfonamide(Formula N′-2, X=3-toluenesulfonamide), 1.19 g, was reduced bynon-critical variations of PREPARATION 49 to give pureN-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxopropyl]phenyl]-4-methyl-benzenesulfonamide(Formula N′-3, X=3-sulfonamide, 0.84 g, m.p. 180-181°.

EXAMPLE 31

N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxypropyl]phenyl-4-methylbenzenesulfonamide(Formula N′-4, X=3-toluenesulfonamide). Refer to Chart N′.

N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxopropyl]phenyl]-4-methyl-benzenefulfonamide(Formula N′-3, X=3-toluenesulfonamide) was reduced by makingnon-critical variations in EXAMPLE 12 to yieldN-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxypropyl]phenyl-4-methylbenzenesulfonamide(0.27 g, m.p. 183°), Formula N′-3, X=3-toluenesulfonamide.

NMR (CDCl₃) 2.27 (S, 3, CH₃), 2.30 (s, 3, CH₃), 2.42 (S, 3, CH₃), 4.85(t, 1, CH), 6.85-7.20 (m, 7, ArH), 7.60-7.69 (m, 2, ArH, CH).

MS m/z 455 (M⁺), 437 (M⁺—H₂O), 325, 310, 282, 267, 191, 177, 165, and154.

IR (mull) 3460, 3024, 2796, 2700, 1608, 1591, 1448, 1434, 1326, and 1151cm⁻¹.

EXAMPLE 32

(E)-N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-1-propenyl]phenyl-4-methylbenzenesulfonamide(Formula N′-5, X=3-toluenesulfonamide). Refer to Chart N′.

(E)-N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxo-1-propenyl]-4-methylbenzenesulfonamide(Formula N′-2, X=3-toluenesulfonamide), 0.835 g, was reduced with LiAlH₄by making non-critical variations in EXAMPLE 23 to produce(E)-N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-1-propenyl]phenyl-4-methylbenzenesulfonamide(Formula N′-5-, X=3-toluenesulfonamide), m.p. 177-179° dec.

Anal. Calcd for C₂₃H₂₃N₃O₃S₂. C, 60.90; H, 5.11; N, 9.26; S, 14.14.Found: C, 60.50; H, 5.09; N, 9.24; S, 13.96.

IR (mull) 3182, 3117, 3072, 1601, 1585, 1331, 1312, 1304, 1236, 1153,1093, and 1079 cm⁻¹.

MS m/z 453 (M⁺), 435, 301, 280, 265, 253, 191, 179, 165, 153, 146, and91.

NMR (DMSO) δ 2.31 (S, 1, CH₃), 2.37 (S, 1, CH₃), 2.59 (S, 1, CH₃), 5.53(d, 1, OH), 5.64 (t, 1, CH), 6.51 (q, J=5, 16 Hz, 1, CH), 6.62, (d, J=16Hz, 1, CH), 7.0-7.25 (m, 6, ArH), 7.6-7.7 (m, 3, ArH, CH), 9.26 (S, 1,NH).

PREPARATION 57

(E)-N-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxo-1-propenyl]-phenyl-4-methylbenzenesulfonamide(Formula N′-2, X=2-toluenesulfonamide). Refer to Chart N′.

1-(2,3-Dimethylimidazo[2,1-b]-thiazol-5-yl)-ethanone (Formula N′-1),0.97 g, was condensed with the toluene sulfonamide of2-aminobenzaldehyde (1.51 g), prepared by a modification of theprocedure described by A. T. Hawson et al., J. Chem. Soc. Perkin 1, 1565(1991), according to a non-critical variation of PREPARATION 15 to yieldpure(E)-N-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxo-1-propenyl]-phenyl-4-methylbenzenesulfonamide,m.p. 198-199°, as a chloroform solvate, Formula N′-2,X=2-toluenesulfonamide.

Anal. Calcd for C₂₃H₂₁N₃O₂S₂.CH₃Cl₃. C, 50.49; H, 3.88; Cl, 18.63; N,7.36; S, 11.23.

Found: C, 50.40; H, 3.80; Cl, 19.22; N, 7.32; S, 11.32.

MS m/z 296 (M⁺), 278, 268, 254, 234, 203, 196, 197, 179, and 152.

IR (mull) 3098, 3072, 3059, 1646, 1590, 1484, 1426, 1364, 1338, 1204,and 1171 cm⁻¹.

NMR (DMSO) δ 2.27 (S, 3, CH₃), 2.42 (S, 3, CH₃), 2.67 (S, 3, CH₃),7.04-7.16 (m, 4, ArH, CH═), 7.27 (m, 3, ArH, CHCl₃), 7.53 (d, J=8 Hz, 2,ArH), 7.73 (m, 1, ArH), 7.90 (d, J=16 Hz, 1, CH₃), 8.10 (S, 1, CH), 9.76(S, 1, NH).

PREPARATION 58

N-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxopropyl]phenyl]-4-methylbenzenesulfonamide(Formula N′-3, X=2-toluenesulfonamide). Refer to Chart N′.

(E)-N-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxo-1-propenyl]-phenyl-4-methylbenzenesulfonamide(Formula N′-2, X=2-toluenesulfonamide), 1.2 g, was reduced toN-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxopropyl]phenyl]-4-methylbenzenesulfonamide(Formula N′-3, X=2-toluenesulfonamide, 0.63 g, m.p. 168-169°, throughnon-critical variations in PREPARATION 48.

NMR (CDCl₃) δ 2.35 (S, 1, CH₃), 2.38 (S, 1, CH₃), 2.55 (t, 2, CH₂), 2.63(S, 3, CH₃), 3.10 (t, 2, CH₂), 7.05-7.25 (m, 5, ArH), 7.45 (d, J=9 Hz,1, ArH), 7.62 (d, J=9 Hz, 2, ArH), 8.55 (S, 1, CH).

EXAMPLE 33

N-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-propyl]phenyl-4-methylbenzensulfonamide(Formula N′-4, X=2-toluenesulfonamide). Refer to Chart N′.

N-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-oxopropyl]phenyl]-4-methylbenzenesulfonamide(Formula N′-3, X=2-toluenesulfonamide) was reduced by non-criticalvariations in EXAMPLE 12 toN-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-propyl]phenyl-4-methylbenzensulfonamide(Formula N′-4, X=2-toluenesulfonamide) (0.36 g), m.p. 207-208°.

Anal. Calcd for C₂₃H₂₅N₃O₃S₂. C, 60.63; H, 5.52; N, 9.22; S, 14.08.Found: C, 60.60; H, 5.62; N, 9.20; S, 14.06.

MS m/z 455 (M⁺), 437, 282, 256, 195, 181, 165, 153, 130, and 129.

IR (mull) 3170, 1341, 1328, 1165, 1159, 1142, 1093, and 1032 cm⁻¹.

NMR (DMSO) 2.23 (S, 3, CH₃), 2.37 (S, 3, CH₃), 2.48 (S, 3, CH₃), 4.70(m, 1, CH), 5.80 (d, 1, OH), 7.0-7.3 (m, 6, ArH), 7.57 (m, 2, ArH), 7.70(S, 1, CH).

PREPARATION 59

3-(2,3-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=2,3-difluoro). Refer to Chart N.

1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)ethanone(Formula N-4), 1.87 g and 2,3-difluorobenzaldehyde (1.39 g) werecondensed by non-critical variations in PREPARATION 15 to provide3-(2,3-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=2,3-difluoro), 1.35 g, m.p. 193-195°.

Anal. Calcd for C₁₉H₁₆F₂N₂SO. C, 63.67; H, 4.50; N, 7.82; S, 8.95.Found: C, 63.65; H, 4.49; N, 7.41; S, 8.65.

MS m/z 358 (M⁺), 339, 330, 329, 311, 301, 245, 231, 219, 203, and 191.

IR (mull) 1657, 1484, 1420, 1359, 1309, 1285, 1194, and 1038 cm⁻¹.

NMR (CDCl₃) δ 1.84 (m, 6, CH₂), 2.40 (m, 2, CH₂), 3.47 (m, 2, CH₂), 7.15(m, 2, ArH), 7.38 (m, 1, ArH), 7.44 (d, J=16 Hz, 1, CH), 7.84 (d, J=16Hz, 1, CH), 8.12 (S, 1, CH).

PREPARATION 60

3-(2,3-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula N-6, X=2,3-difluoro). Refer to Chart N.

3-(2,3-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=2,3-difluoro) was reduced with NaHTe according tonon-critical variations in PREPARATION 49 to provide 0.25 g of3-(2,3-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-yl)-1-propanone,m.p. 108-110°, Formula N-6, X=2,3-difluoro).

MS m/z 360 (M⁺), 341, 313, 247, 233, 219, 193, 192, and 127.

NMR (CDCl₃) δ 1.81 (m, 6, CH₂), 2.76 (m, 2, CH₂), 3.14 (m, 4, CH₂), 3.45(m, 2, CH), 7.0 (m, 3, ArH), 7.99 (S, 1, CH).

EXAMPLE 34

α-[2-(2,3-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazothiazol-3-methanol(Formula N-7, X=2,3-difluoro). Refer to Chart N.

3-(2,3-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula N-6, X=2,3-difluoro), 0.15 g, was reduced with NaBH₄ accordingto non-critical variations in EXAMPLE 12 to produceα-[2-(2,3-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazothiazol-3-methanol(Formula N-7, X=2,3-difluoro), m.p. 158-159°.

Anal. Calcd for C₁₉H₂₀FN₂OS. C, 62.96; H, 5.56; N, 7.73; S, 8.85. Found:C, 62.55; H, 5.58; N, 7.54; S, 8.62.

MS m/z 362 (M⁺), 344, 313, 231, 221, 205, 193, and 165.

IR (mull) 3199, 3130, 1490, 1481, 1445, 1311, 1283, and 1276 cm⁻¹. NMR(CDCl₃) δ 1.81 (m, 6, CH₂), 2.26 (m, 2, CH₂), 2.4-3.1 (m, 5, CH₂), 3.32(m, 1, CH₂), 4.92 (t, 1, CH), 6.90-7.12 (m, 4, ArH, CH).

PREPARATION 61

3-(4-Methoxyphenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula N-5, X=4-methoxy). Refer to Chart N.

1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-ethanone(Formula N-4), 0.44 g, and anisaldehyde (0.5 mL) were condensedaccording to non-critical variations in PREPARATION 15 to produce3-(4-Methoxyphenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one,0.65 g, (Formula N-5, X=4-methoxy), m.p. 180-187°.

Anal. Calcd for C₂₀H₂₀N₂O₂S. C, 68.16; H, 5.72; N, 7.95; S, 9.10. Found:C, 67.87; H, 5.81; N, 8.10; S, 8.94.

MS m/z 352 (M⁺), 337, 323, 309, 281, 231, 218, 190, 161, 133, and 121.

IR (mull) 1649, 1588, 1574, 1511, 1421, 1360, 1250, 1180, 1168 and 1033cm⁻¹.

NMR (CDCl₃) δ 1.81 (m, 6, CH₂), 2.76 (m, 2, CH₂), 3.43 (m, 2, CH₂). 3.86(S, 3, OCH₃), 6.93 (d, J=9 Hz, 2, ArH), 7.18 (d, J=16 Hz, 1, CH), 7.57(d, J=9 Hz, 2, ArH), 7.75 (d, J=16 Hz, 1, CH), 8.07 (S, 1, CH)

PREPARATION 62

3-(4-Methoxyphenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula N-3, X=4-methoxy). Refer to Chart N.

3-(4-Methoxyphenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one,0.18 g, (Formula N-5, X=4-methoxy) was reduced with NaHTe usingnon-critical variations of PREPARATION 49 to yield pure3-(4-Methoxyphenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone,(0.15 g), m.p., 94-96°, (Formula N-6, X=4-methoxy).

Anal. Calcd for C₂₀H₂₂N₂O₂S. C, 67.77; H, 6.26; N, 7.90; S, 9.05. Found:C, 67.42; H, 6.38; N, 7.78; S, 9.01.

MS m/z 354 (M⁺), 247, 233, 219, 192, 134, and 121.

IR (mull) 1663, 1513, 1426, 1303, 1267, 1246, 1195, 1181, 1032, and 824cm⁻¹.

NMR (CDCl₃) δ 1.81 (m, 6, CH₂), 2.77 (m, 2, CH₂), 3.02 (m, 2, CH₂), 3.12(m, 2, CH₂), 3.40 (m, 2, CH₂), 3.79 (S, 3, OCH₃), 6.83 (d, J=9 Hz, 2,ArH), 7.15 (d, J=9 Hz, 2, ArH), 7.98 (S, 1, CH).

EXAMPLE 35

α-[2-(4-methoxyphenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol(Formula N-7, X=4-methoxy). Refer to Chart N.

3-(4-Methoxyphenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula N-6, X=4-methoxy), (0.12 g), was reduced with NaBH₄ bynon-critical variations of EXAMPLE 12 to giveα-[2-(2,3-methoxyphenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazothiazol-3-methanol(Formula N-7, X=4-methoxy), 0.09 g, m.p. 124-125°, after crystallizationfrom acetonitrile solution.

Anal. Calcd for C₂₀H₂₄N₂O₂S. C, 67.39; H, 6.79; N, 7.86; S, 9.00. Found:C, 67.19; H, 6.76; N, 7.79; S, 9.04.

MS m/z 356 (M⁺), 329, 221, 205, 193, 165, 150, and 121.

IR (mull) 3190, 3137, 1513, 1274, 1180, 1072, 1040, and 822 cm⁻¹.

NMR (CDCl₃) δ 1.82 (m, 6, CH₂), 2.33 (m, 2, CH₂), 2.63-3.02 (m, 5, CH₂),3.30 (m, 1, CH₂), 3.80 (S, 3, CH₃O), 6.86 (d, J=9 Hz, 2, ArH), 7.12 (d,J=9 Hz, 2, ArH), 7.26 (S, 1, CH).

EXAMPLE 36

α-[2-(4-Methoxyphenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol(Formula N-8, X=4-methoxy). Refer to Chart N.

3-(4-Methoxyphenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazothiazol-3-yl)-2-propene-1-one(Formula N-5, X=4-methoxy) was reduced with NaBH₄ by non-criticalvariations of EXAMPLE 22 to provideα-[2-(4-Methoxyphenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol(Formula N-8, X=4-methoxy), 0.15 g, m.p. 188-189°.

Anal. Calcd for C₂₀H₂₂N₂OS. C, 67.77; H, 6.23; N, 7.90; S, 9.05. Found:C, 67.47; H, 6.23; N, 7.81; S, 9.11.

MS m/z 354 (M⁺), 337, 325, 247, 246, 233, 220, 205, 192, 187, 134, and121.

IR (mull) 3132, 3119, 3071, 1609, 1511, 1447, 1437, 1315, 1302, 1300,1274, 1251, 1180, 1174, 1145, 1094, and 1033 cm⁻¹.

NMR (CDCl₃) δ 1.82 (m, 6, CH₂), 2.71 (m, 2, CH₂), 3.10 (m, 1, CH₂), 3.36(M, 1, CH₂), 3.83 (S, 3, OCH₃), 5.65 (d, 1, CH), 6.41 (q, 1, CH), 6.67(d, 1, CH), 6.88 (d, J=9 Hz, 1, ArH), 7.36 (d, J=9 Hz, 1, ArH).

PREPARATION 63

3-(2-Napthalenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula O-2). Refer to Chart O.

1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)ethanone(Formula O-1), 1.37 g, was condensed with 2-napthaldehyde bynon-critical variations of EXAMPLE 15 to yield3-(2-Napthalenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula O-2), 2.24 g, m.p. 185-188°.

Anal. Calcd for C₂₃H₂₀N₂OS. C, 74.16; H, 5.41; N, 7.52; S, 8.61. Found:C, 73.81; H, 5.47; N, 7.54; S, 8.58.

MS m/z 372 (M⁺), 355, 343, 315, 245, 231, 152 and 142.

IR (mull) 3096, 3066, 3056, 3036, 3008, 1650, 1600, 1586, 1421, 1367,1346, 1301, 1269, and 1197 cm⁻¹.

PREPARATION 64

3-(2-Napthalenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula O-3, X=H). Refer to Chart O.

2-Napthalenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula O-2, X=H), 0.74 g, was reduced according to non-criticalvariation in PREPARATION 49 to provide3-(2-Napthalenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula O-3), m.p. 76-78° after acetonitrile crystallization of thesilica gel eluted product.

Anal. Calcd for C₂₃H₂₂N₂OS. C, 73.77; H, 5.92; N, 7.48; S, 8.56. Found:C, 73.72; H, 6.14; N, 7.40; S, 8.51.

MS m/z 374 (M⁺), 247, 233, 219, 192, 154, and 141.

IR (mull) 3318, 3105, 3055, 3018, 1667, 1500, 1426, 1356, 1310, 1184,and 1175 cm⁻¹.

NMR (CDCl₃) δ 1.80 (m, 6, CH₂), 2.75 (m, 2, CH₂), 3.23 (m, 4, CH₂), 3.42(m, 2, CH₂), 7.45 (m, 3, ArH), 7.67 (S, 1, ArH), 7.78 (m, 3, ArH), 8.00(S, 1, CH).

EXAMPLE 37

α-[2-(2-Naphthalenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula O-4). Refer to Chart O.

3-(2-Napthalenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula O-3), 0.10 g, was reduced with NaBH₄ by non-critical variationsof EXAMPLE 12 to yield pure α-[2-(2-Naphthalenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula O-4, X=H), m.p. 124-127°.

Anal. Calcd for C₂₃H₂₄N₂OS. C, 73.37; H, 6.42; N, 7.44; S, 8.52. Found:C, 72.43; H, 6.62; N, 7.50; S, 8.36.

MS m/z 376 (M⁺), 349, 332, 235, 234, 221, 193 and 141.

IR (mull) 3201, 3140, 3121, 1631, 1608, 1599, 1446, 1431, 1310, 1280,1271, 1163, and 1151 cm⁻¹.

NMR (CDCl₃) δ 1.75 (m, 6, CH₂), 2.34 (m, 2, CH₂), 2.65 (m, 2, CH₂),2.80-3.15 (m, 3, CH₂), 3.28 (m, 1, CH₂), 4.90 (t, 1, CH), 7.05 (S, 1,CH), 7.3-7.5 (m, 3, ArH), 7.64 (S, 1, ArH), 7.78 (m, 3, ArH).

PREPARATION 65

3-(2-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula P-2, X=0). Refer to Chart P.

3-(3-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-ethanone(Formula P-1), 3.51 g, was condensed with 2-Furaldehyde (1.99 g) bynon-critical variations of PREPARATION 15 to give3-(2-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula P-2, X=0), m.p. 161-162°.

Anal. Calcd for C₁₇H₁₆N₂O₂S. C, 65.36; H, 5.16; N, 8.97; S, 10.26.Found: C, 65.26; H, 5.17; N, 8.98; S, 10.20.

MS m/z 312, 295, 284, 283, 269, 255, 231, 218, 203, and 190.

IR (mull) 3126, 3114, 3011, 1653, 1598, 1557, 1551, 1497, 1354, 1349,1303, 1292, 1267, 1203, and 1018 cm⁻.

NMR (CDCl₃) 1.86 (m, 6, CH₂), 2.78 (m, 2, CH₂), 3.46 (m, 2, CH₂), 6.51(q, 1, CH), 5.67 (d, J=3.5 Hz, 1, CH), 7.23 (d, J=15 Hz, 1, CH), 7.53(d, 1, CH), 7.55 (d, J=15 Hz, 1, CH).

EXAMPLE 38

α-[2-(2-Furanyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula P-4, X=0). Refer to Chart P.

3-(2-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl-2-propene-1-one(Formula P-2, X=0), 0.20 g, was reduced by non-critical variations ofEXAMPLE 22 to yield aα-[2-(2-Furanyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula P-4, X=0), 0.15 g, m.p. 177-180° after crystallization fromisopropanol solution.

Anal. Calcd for C₁₇H₁₈N₂O₂S. C, 64.94; H, 5.77; N, 8.91; S, 10.20.Found: C, 64.89; H, 5.94; N, 8.88; S, 10.99.

MS m/z 314 (M⁺), 297, 285, 269, 257, 233, 221, 219, 193, 192, 179, and147.

IR (mull) 3112, 3099, 1610, 1543, 1489, 1446, 1439, 1322, 1311, 1276,1147, 1097, and 1012 cm⁻¹.

NMR (CDCl₃) δ 1.79 (m, 6, CH₂), 2.68 (m, 2, CH₂), 3.07 (m, 1, CH₂), 3.35(m, 1, CH₂), 3.62 (b, 1, OH), 5.63 (d, J-4.4 Hz, 1, CH), 6.27 (d, J=3.3Hz, 1, CH), 6.39 (q, 1, CH), 6.44 (q, J=4.4 Hz, J=16 Hz, 1, CH), 6.57(d, J=16 Hz, 1, CH), 6.95 (S, 1, CH), 7.38 (d, 1, CH).

EXAMPLE 39

α-[2-(2-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula P-5, X=0). Refer to Chart P.

3-(2-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-propene-1-one(Formula P-2, X=0), 0.94 g, was reduced with LiAlH₄ by non-criticalvariations of EXAMPLE 23 to provideα-[2-(2-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula P-5, X=0), after two crystallizations from ethanol.

Anal. Calcd for C₁₇H₂₀N₂O₂S. C, 64.53; H, 6.37; N, 8.85; S, 10.13.Found: C, 64.56; H, 6.20; N, 8.81; S, 10.14.

MS m/z 316 (M⁺), 299, 297, 287, 285, 269, 221, 205, and 193.

IR (mull) 3186, 3139, 3118, 1610, 1599, 1506, 1434, 1316, 1277, and 1160cm⁻¹.

NMR (CDCl₃) δ 1.80 (m, 6, CH₂), 2.28 (M, 2, CH₂), 2.50-2.80 (m, 4, CH₂),2.75-3.05 (m, 3, CH₂), 3.30 (m, 1, CH₂), 4.90 (m, 1, CH), 6.05 (m, 1,CH), 6.29 (m, 1, CH), 7.40 (S, 1, CH), 7.26 (d, 1, CH).

PREPARATION 66

3-(3-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula P-2, X=0). Refer to Chart P.

1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-ethanone(Formula P-1), 1.87 g, was reacted with 3-furaldehyde (0.73 mL) bynon-critical variations of PREPARATION 15 to give3-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-propene-1-one(Formula P-2, X=0), 1.74 g, m.p. 168-170°, after crystallization fromacetonitrile solution.

Anal. Calcd for C₁₇H₁₆N₂O₂S. C, 65.36; H, 5.16; N, 8.97; S, 10.26.Found: C, 65.19; H, 5.21; N, 9.03; S, 10.17.

MS m/z 312 (M⁺), 295, 283, 269, 267, 255, 231, 193, and 121.

IR (mull) 3445, 3142, 3108, 3096, 1654, 1600, 1506, 1448, 1422, 1359,1304, 1271, 1203, and 1161 cm⁻¹.

NMR (CDCl₃) δ 1.86 (m, 6, CH₂), 2.78 (m, 2, CH₂), 3.44 (m, 2, CH₂), 6.71(d, 1, CH), 7.02 (d, J=16 Hz, 1, CH), 7.48 (d, 1, CH), 7.66 (d, J=16 Hz,1, CH), 7.71 (S, 1, CH), 8.06 (S, 1, CH).

PREPARATION 67

3-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula P-3, X=0). Refer to Chart P.

3-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one(Formula P-2, X=0), (0.31 g) was reduced by non-critical variations ofPREPARATION 49 to produce3-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-1-propanone(Formula P-3, X=0), 0.24 g, m.p. 111-114°.

Anal. Calcd for C₁₇H₁₈N₂O₂S. C, 64.94; H, 5.77; N, 8.91; S, 10.20.Found: C, 64.98; H, 5.82; N, 8.89; S, 10.12.

MS m/z 314 (M⁺), 297, 286, 285, 271, 257, 219, 205, and 192.

IR (mull) 3308, 3176, 3139, 3121, 3098, 1665, 1509, 1446, 1424, 1410,1305, 1204, 1199, and 1026 cm⁻¹.

NMR (CDCl₃) δ 1.81 (m, 6, CH₂), 2.72 (m, 2, CH₂), 2.90 (m, 2, CH₂), 3.06(m, 2, CH₂), 3.40 (m, 2, CH₂, 6.30 (d, 1, CH), 7.26 (d, 1, CH), 7.35 (S,1, CH), 8.00 (S, 1, CH).

EXAMPLE 40

α-[2-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula P-5, X=0). Refer to Chart P.

3-(3-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl-1-propanone(Formula P-3, X=0), 0.115 g, was reduced with NaBH₄ by non-criticalvariations in EXAMPLE 12 to yieldα-[2-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol(Formula P-5, X=0), m.p. 153-155°.

Anal. Calcd for C₁₇H₂₀N₂O₂S. C, 64.53; H, 6.37; N, 8.85; S, 10.13.Found: C, 64.22; H, 6.44; N, 8.80; S, 9.93.

MS m/z 316 (M⁺), 299, 298, 297, 287, 245, 234, 221, 205, 203, and 193.

IR (mull) 3190, 3134, 1501, 1445, 1367, 1315, 1278, 1162, 1155, 1070,and 1021 cm⁻¹.

NMR (CDCl₃) δ 1.82 (m, 6, CH₂), 2.20 (m, 2, CH₂), 2.67 (m, 4, CH₂), 3.0(m, 1, CH₂), 3.30 (m, 1, CH₂), 4.90 (t, 1, CH), 6.30 (d, 1, CH), 7.12(d, 1, CH), 7.26 (S, 1, CH), 7.40 (S, 1, CH).

PREPARATION 68

3-[2-Furanyl)-2,3-dimethylimidazo[2,1-b]thiazol-3-yl]-2-propene-1-one(Formula Q-2, X=0). Refer to Chart Q.

1-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl]ethanone (Formula Q-1), 2.92g, was condensed with 2-furaldehyde (2.0 mL) by non-critical variationsof PREPARATION 15 to produce3-[(2-Furanyl)-2,3-dimethylimidazo[2,1-b]thiazol-3-yl]-2-propene-1-one(Formula Q-2, X=0).

NMR (CDCl₃) δ 2.37 (S, 3, CH₃), 2.67 (S, 3, CH₃), 6.51 (m, 1, CH), 6.67(m, 1, CH), 7.22 (d, J=16 Hz, 1, CH), 7.52 (m, 3, CH), 8.07 (S, 1, CH).

EXAMPLE 41

α-[2-(2-Furanyl)ethenyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol(Formula Q-3, X=0). Refer to Chart Q.

3-[(2-Furanyl)-2,3-dimethylimidazo[2,1-b]thiazol-5-yl]2-propene-1-one(0.20 g), Formula Q-2, X=0), was reduced with NaBH₄ by non-criticalvariations in EXAMPLE 22 to yieldα-[2-(2-Furanyl)ethenyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol(Formula Q-3, X=0), 0.15 g, m.p. 149-150°.

Anal. Calcd for C₁₄H₁₄N₂O₂S. C, 61.29; H, 5.14; N, 10.21; S, 11.69.Found: C, 61.19; H, 5.26; N, 10.20, S, 11.62.

MS m/z 274 (M⁺), 257, 245, 229, 217, 193, 181, 179, 165, and 152.

IR (mull) 3145, 3115, 3033, 1546, 1451, 1432, 1323, 1298, 1249, 1143,1096, and 1015 cm⁻¹.

NMR (CDCl₃) δ 2.29 (S, 3, CH₃), 2.56 (S, 3, CH₃, 5.65 (d, 1, CH), 6.28(m, 1, CH), 6.39 (m, 1, CH), 6.45 (q, 1, CH), 6.53 (d, J=16, 1, CH),6.98 (S, 1, CH), 7.38 (d, 1, CH).

EXAMPLE 42

α-[2-(2-Furanyl)ethyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol(Formula Q-4, X=0). Refer to Chart Q.

3-[(2-Furanyl)-2,3-dimethylimidazo[2,1-b]thiazol-3-yl]-2-propene-1-one,Formula Q-2, X=0), 0.272 g, was reduced with LiAlH by non-criticalvariations of EXAMPLE 22 to provide pureα-[2-(2-Furanyl)ethyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol(Formula Q-4, X=0), 0.02 g, m.p. 144-145°.

PREPARATION 69

G1-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-3-phenyl-1-propanone(Formula R-3, X=H).

(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl) ethanone, 0.94 g, (Formula R-1)was converted to the t-butyl-dimethylenol silane usingdimethyl-tertbutyl chlorosilane (1.10 g) in the procedure described byP. Cazeau et al. (Tetrahedron, 43, 2075 (1987)). The crude enol silaneproduct was purified by silica gel chromatography to yield pure enolsilane, 1.0 g, (Formula R-2). Benzaldehyde (0.34 g) in methylenechloride (10 mL) at −78° was treated with BF₃ ethereate (0.461 g) inCH₂Cl₂ (15 mL). After 20 minutes, a solution of enol silane (FormulaR-2, 1.0 g) in CH₂Cl₂ (10 mL) was added dropwise during 30 minutes.After 3 hours reaction, the solution was brought to −10° to −15° andmaintained for 18 hours. The reaction solution was quenched into 5%NaHCO₃ solution and the residue (0.94 g) from evaporation of theextraction solvent was purified by silica gel chromatography to yieldpure1-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-3-phenyl-1-propanone(Formula R-3, X=H), m.p. 113°.

NMR (CDCl₃) δ 2.37 (S, 3, CH₃), 2.65 (S, 3, CH₃), 3.20 (m, 2, CH), 5.40(m, 1, CH), 7.27-7.50 (m, 5, ArH), 7.96 (S, 1, CH).

EXAMPLE 43

1-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-phenyl-1,3-propanediol(Formula R-4, X=H).

1-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-3-phenyl-1-propanone(Formula R-3, X=H), 0.08 g, in toluene (10 mL) was treated with 1Mdiisobutylaluminum hydride (1.0 mL) and reacted for 1.25 hours. Thesolution was quenched into 5% citric acid, the mixture was extractedwith ethyl acetate and the citric acid solution was neutralized withNaOH. Extraction of product from the neutralized solution gave pure1-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-phenyl-1,3-propanediol(Formula R-4, X=H), 0.04 g, m.p. 152-153° after crystallization fromCH₂Cl₂/CH₃CN solution.

MS m/z 302 (M⁺), 284, 267, 207, 195, 181, 165, and 153.

NMR (CDCl₃) 2.27 (S, 3, CH₃), 2.46 (S, 3, CH₃), 5.03-5.35 (m, 2, CH),7.0 (S, 1, CH), 7.20-7.45 (m, 5, ArH).

TABLE 1 Protease Inhibition by 2,3-Dimethylimidazo[2,1-b]Thiazole5-Methanol Derivatives

% Protease Inhibition Compound 10 3.3-3.7 1.1-1.3 Ki of R μM μM μM (nM)Ex. 11 CH₂CH₂C₆H₅ 112 109 96 120 Ex. 12 CH═CHC₆H₅ 110 103 63 567 ± 282Ex. 1  C≡C—C₆H₅  16 <10 — — Ex. 2  CH₂C₆H₅  86  27 <10   — Ex. 3 CH₂CH₂CH₂C₆H₅ 115  72 16 246 ± 73 

TABLE 2 Protease Inhibition by 3-Methylimidazothiazole-5-MethanolDerivatives

% Protease Inhibition Compound 10 3.3-3.7 1.1-1.3 of R X μM μM μM Ex. 8 CH₂CH₂C₆H₅ H 79 32 <10 Ex. 6  CH₂CH(CH₃)C₆H₅ H 51 <10   <10 Ex. 9 CH₂CH₂C₆H₄Br H 83 22 <10 Ex. 10 (CH₂)₄C₆H₅ H 58 12 <10

TABLE 3 Protease Inhibition by Imidazothiazole Tertiary Carbinols

% Protease Inhibition Compound 10 3.3-3.7 1-1.2 of R₁ R₂ R₃ μM μM μM Ex.7 H CH₃ CH₂CH₂C₆H₅   14.5 <10 <10 Ex. 5 H CH₃ CH═CHC₆H₅ <10   <10 <10 **48.93% inhibition at 30 μM

TABLE 4 In Vitro Protease Activities of Imidazo[2,1-b]thiazoles ProteaseInhibition % Inhibition Ki (μM) (nM) A. R₁ = CH₂CH₂C₆H₅ Ex. 8

 32 (3.3) <10 (1.1) — Ex. 11

 94 (3.3)   92 (1.2) 120 Ex. 13

 85 (3.3)   39 (1.1) — Ex. 14

102 (3.3)   73 (1.1) 68 ± 14 Ex. 15

 94 (3.3)   57 (1.1) 57 ± 14 Ex. 17

 88 (3.3)   62 (1.1) 72 ± 26 Ex. 18

 28 (3.3) <10 (1.1) — B. R₂ = CH₂CH₂CH₂CH₂C₆H₅ Ex. 10

 12 (3.3) <10 (1.1) — Ex. 16

 98 (3.3)   54 (1.1) 227 ± 42 

TABLE 5 HIV-1 Protease Inhibition byImidazo[2,1-b]benzothiazole-α-(2-phenylethyl)-methanol Derivatives % HIVCompound Structures Protease Inhibition of R = CH₂CH₂C₆H₅ 10 μM 3.3 μMEx. 18

94 28 Ex. 19

92 59 Ex. 20

88 43 Ex. 21

93 80

TABLE 6 HIV Protease Inhibition by Substituted Aryl- and Heteroaryl,Imidazo[2,1-b]thiazole-α-(2-phenylethyl) methanol Derivatives

COM- POUND PROTEASE OF INHIBITION EXAM- 10 3.3 1.1 Ki PLE R μM μM μM(nM) 23

75 64 35 33 24

84 77 53 89 26

89 80   4.8 — 27

96 98 55 — 28

99 88 64 — 29

94 70 24 — 34

100  99 58 — 35

92 81 63 — 37

94 80 51 — 39

92 85 54 —

TABLE 7 HIV Protease Inhibition by Substituted Aryl- and HeteroarylImidazo[2,1-b]thiazole-α-(2-phenylethenyl)Methanol Derivatives

PROTEASE COMOUND INHIBITION OF 10 3.3 1.1 EXAMPLE R μM μM μM 22

66   57 24 25

21   33 23 30

24 <10 — 36

42   52 15 38

98   60 12

TABLE 8 HIV Protease Inhibition by Substituted Aryl- and Heteroaryl2,3-dimethylimidazo[2,1-b]thiazole-α-(2-phenylethyl) methanolDerivatives

PROTEASE COMPOUND INHIBITION OF 10 3.3 1.1 EXAMPLE R μM μM μM 31

98 68   15 33

97 52 <10 42

92 46 <10

TABLE 9 HIV Protease Inhibition by Substituted Aryl- and Heteroaryl2,3-dimethylimidazo[2,1-b]thiazole-α-(2-phenylethenyl) methanolDerivatives

PROTEASE COMPOUND INHIBITION OF 10 3.3 1.1 EXAMPLE R μM μM μM 32

15 <10 — 41

81   19 —

I claim:
 1. A compound of the formula I

wherein R₁ is —H or —CH₃; wherein R₂ is —H or —CH₃; or wherein R₁ and R₂taken together are

wherein p is 1 to 4 inclusive; or wherein R₆ is a) —H, b) —CH₃, c) —F,or d) —OCH₃; wherein R₃ is a) —CH₂C₆H₅, b) —CH₂CH₂C₆H₅, c)—CH₂CH₂CH₂C₆H₅, d) —CH₂CH₂CH₂CH₂C₆H₅, e) —CH₂CH(CH₃)C₆H₅, f)—CH₂CH₂C₆H₄X, wherein X may occupy either the ortho, meta orpara-positions and is i) F ii) Cl, iii) Br, iv) OCH₂R₁, v) N(CH₃)₂, vi)NHSO₂CH₂R₁, vii) SCH₃ viii) NHCOCH₂R₁, or ix) NHSO₂C₆H₄X₁, wherein X₁ isa. H, b. CH₃, c. F, or d. CN; g) —CH═CH—C₆H₅, (cis or trans); h)—CH≡C—C₆H₅); i) CH═CH—C₆H₃X₂ wherein X₂ is a. F, b. Cl, c. OCH₃, or d.OCH₂O;

wherein CH₂CH₂ is appended to the 1- or 2-positions; or

wherein i) —CH₂CH₂— appended to the 2- or 3-positions, ii) X₃ is a. O,b. S, c. NH, d. NCH₃, and iii) R₇ is a. CH₃, or b. CH₃CH₂; wherein R₄ is—H or —CH₃; and wherein R₅ is —H or —CH₃; provided that when R₁ is —CH₃and R₂ is —H or —CH₃, R₄ is not —H.
 2. The compound of claim 1 whereinR₁ is —H or —CH₃; wherein R₂ is —H or —CH₃; wherein R₃ is a) —CH₂C₆H₅,b) —CH₂CH₂C₆H₅, c) —CH₂CH₂CH₂C₆H₅, d) —CH₂CH₂CH₂CH₂C₆H₅, e)—CH₂CH(CH₃)C₆H₅, f) —CH₂CH₂C₆H₄X, wherein X is i) F, ii) Cl, or iii) Br,g) —CH═CH—C₆H₅, (cis or trans) or h) —C≡C—C₆H₅; wherein R₄ is —H or—CH₃; and wherein R₅ is —H or —CH₃; provided that when R₁ is —CH₃ and R₂is —H or —CH₃, R₄ is not —H.
 3. The compound of claim 1 of the formula Iwherein R₁ and R₂ taken together are

wherein R₆ is a) —H b) —CH₃, c) —F, or d) —OCH₃.
 4. The compound ofclaim 1 of the formula I wherein R₁ and R₂ taken together are

wherein p is 1 to 4 inclusive.
 5. The compound of claim 1 selected fromthe group consisting of:2,3-Dimethyl-α-(2-phenylethynyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylmethyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(3-phenylpropyl)imidazo-[2,1b]thiazole-5-methanol,2,3-Dimethyl-α-Di(2-phenylethyl)imidazo-[2,1-b]thiazole-5-methanol,α,3-Dimethyl-α-(E-2-phenyl-E-ethenyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(2-phenylpropyl)imidazo[2,1-b]thiazole-5-methanol,α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(4-bromophenylethyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(4-phenylbutyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylethenyl)imidazo[2,1-b]thiazole-5-methanol,6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol,5,6,7,8-Tetrahydro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,6,7,8,9-Tetrahydro-α-(2-phenylethyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol,6,7,8,9-Tetrahydro-α-(4-phenylbutyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol,5,6,7,8,9,10-Hexahydro-α-(2-phenylethyl)cyclooct[d]imidazo-[2,1-b]thiazole-3-methanol,α-(2-phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol,7-Methyl-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,7-Fluoro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,7-Methoxy-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,α-[2-(3-Flurophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-imidazo[2,1-b]thiazole-3-methanolα-[2-(3-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(4-Flurophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,[α-[2-(4-Flurophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,]α-[2-(3-Bromophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-2,1-b]thiazol-3-methanol,α-[2-(3-Chlorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,[α-[2-(3,5-Difluorophenyl)ethyl]-1-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazothiazol-3-methanol,]α-[2-(4-dimethylaminophenyl)ethyl-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-2,1-b]thiazol-3-methanol,α-[2-(4-Dimethylaminophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-methanol,N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxypropyl]phenyl-4-methylbenzenesulfonamide,N-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-propyl]phenyl-4-methylbenzensulfonamide,[α-[2-(2,3-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-thiazol-3-methanol,]α-[2-(4-methoxyphenyl)ethyl]6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1b]thiazol-3-methanol,and[α-[2-(4-methoxyphenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-]thiazol-3-methanol,]α-[2-(2-Naphthalenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol],α-[2-(2-Furanyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethenyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol,and α-[2-(2-Furanyl)ethyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol].6. The compound of claim 2 selected from the group consisting of:2,3-Dimethyl-α-(2-phenylethynl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylmethyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(3-phenylpropyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-Di(2-phenylethyl)imidazo-[2,1-b]thiazole-5-methanol,α,3-Dimethyl-α-(E-2-phenyl-E-ethenyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(2-phenylpropyl)imidazo[2,1-b]thiazole-5-methanol,α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol, and3-Methyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(4-bromophenylethyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(4-phenylbutyl)imidazo-[2,1b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylethenyl)imidazo[2,1-b]thiazole-5-methanol,N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxypropyl]phenyl-4-methylbenzenesulfonamide, andN-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-propyl]phenyl-4-methylbenzensulfonamide,[α-[2-(2-Furanyl)ethenyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol,and α-[2-(2-Furanyl)ethyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol].7. The compound of claim 3 selected from the group consisting of: α-(2phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol,7-Methyl-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,7-Fluoro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol, and7Methoxy-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol.
 8. Thecompound of claim 4 selected from the group consisting of:6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol,5,6,7,8-Tetrahydro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,6,7,8,9-Tetrahydro-α-(2-phenylethyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol,6,7,8,9-Tetrahydro-α-(4-phenylbutyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol,5,6,7,8,9,10-Hexahydro-α-(2-phenylethyl)cyclooct[d]imidazo-[2,1-b]thiazole-3-methanol,α-[2-(3-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-imidazo]2,1-b]thiazole-3-methanolα-[2-(3-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(4-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,[α-[2-(4-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,]α-[2-(3-Bromophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-2,1-b]thiazol-3-methanol,α-[2-(3-Chlorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,[α-[2-(3,5-Difluorophenyl)ethyl]-1-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazothiazol-3-methanol,]α-[2-(4-dimethylaminophenyl)ethyl-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-[2,1-b]thiazol-3-methanol,α-[2-(4-Dimethylaminophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-methanol,α-[2-(2,3-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-thiazol-3-methanol,]α-[2-(4-methoxyphenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1b]thiazol-3-methanol,and[α-[2-(4-methoxyphenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol,]α-[2-(2-Naphthalenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol[,α-[2-(2-Furanyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol.9. A method for treatment of mammals infected with a retrovirus, saidmethod comprising administering to a mammal infected with saidretrovirus a therapeutically effective amount of a compound of theformula I

wherein R₁ is —H or —CH₃; wherein R₂ is —H or —CH₃; or wherein R₁ and R₂taken together are

wherein p is 1 to 4 inclusive; or wherein R₆ is a) —H b) —CH₃, c) —F, ord) —OCH₃; wherein R₃ is a) —CH₂C₆H₅, b) —CH₂CH₂C₆H₅, c) —CH₂CH₂CH₂C₆H₅,d) —CH₂CH₂CH₂CH₂C₆H₅, e) —CH₂CH(CH₃)C₆H₅, f) —CH₂CH₂C₆H₄X, wherein X mayoccupy either the ortho, meta or para-positions and is i) F, ii) Cl,iii) Br, iv) OCH₂R₁, v) N(CH₃)₂, vi) NHSO₂CH₂R₁, vii) SCH₃ viii)NHCOCH₂R₁, or ix) NHSO₂C₆H₄X₁, wherein X₁is a. H, b. CH₃, c. F, or d.CN; g) —CH═CH—C₆H₅, (cis or trans); h) —CH≡C—C₆H₅); i) —CH═CH—C₆H₃X₂wherein X₂ is a. F, b. Cl, c. OCH₃, or d. —O—CH₂O;

wherein CH₂CH₂ is appended to the 1- or 2-positions; or

wherein i) —CH₂CH₂— appended to the 2- or 3- positions, ii) X₃ is a. O,b. S, c. NH, and d. —NCH₃; iii) R₇ is a. CH₃, or b. CH₃CH₂; wherein R₄is —H or —CH₃; and wherein R₅ is —H or —CH₃; provided that when R₁ is—CH₃ and R₂ is —H or —CH₃, R₄ is not —H.
 10. The method of claim 9wherein the compound is selected from the group consisting of:2,3-Dimethyl-α-(2-phenylethynyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylmethyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(3-phenylpropyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylethyl)imidazo-[2,1-b]thiazole-5-methanol,α,3-Dimethyl-α-(E-2-phenyl-E-ethenyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(2-phenylpropyl)imidazo[2,1-b]thiazole-5-methanol,α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(4-bromophenylethyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(4-phenylbutyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylethenyl)imidazo[2,1-b]thiazole-5-methanol,6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol,5,6,7,8-Tetrahydro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,6,7,8,9-Tetrahydro-α-(2-phenylethyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol,6,7,8,9-Tetrahydro-α-(4-phenylbutyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol,5,6,7,8,9,10-Hexahydro-α-(2-phenylethyl)cyclooct[d]imidazo-[2,1-b]thiazole-3-methanol,α-(2-phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol,7-Methyl-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,7-Fluoro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,7-Methoxy-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,α[2-(3-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-imidazo[2,1-b]thiazole-3-methanolα[2-(3-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(4-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,[α-[2-(4-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,]α-[2-(3-Bromophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-2,1-b]thiazol-3-methanol,α-[2-(3-Chlorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,[α[2-(3,5-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazothiazol-3-methanol,]α-[2-(4-dimethylaminophenyl)ethyl-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-[2,1-b]thiazol-3-methanol,α-[2-(4-Dimethylaminophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-methanol,N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxypropyl]phenyl-4-methylbenzenesulfonamide,N-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-propyl]phenyl-4-methylbenzensulfonamide,[α-[2-(2,3-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-thiazol-3-methanol,]α-[2-(4-methoxyphenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol,and[α-[2-(4-methoxyphenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol,]α-[2-(2-Naphthalenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol],α-[2-(2-Furanyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethenyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol,and α-[2-(2-Furanyl)ethyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol].11. A pharmaceutical composition for use in treatment of a mammalinfected with a retrovirus, said composition comprising apharmaceutically acceptable solvent, diluent, adjuvant or carrier and,as the active ingredient, from about 0.1 mg to 100 mg per kg of bodyweight per day of a compound of the formula I

wherein R₁ is —H or —CH₃; wherein R₂ is —H or —CH₃; or wherein R₁ and R₂taken together are

wherein p is 1 to 4 inclusive; or wherein R₆ is a) —H b) —CH₃, c) —F, ord) —OCH₃; wherein R₃ is a) —CH₂C₆H₅, b) —CH₂CH₂C₆H₅, c) —CH₂CH₂CH₂C₆H₅,d) —CH₂CH₂CH₂CH₂C₆H₅, e) —CH₂CH(CH₃)C₆H₅, f) —CH₂CH₂C₆H₄X, wherein X mayoccupy either the ortho, meta or para positions and is i) F, ii) Cl,iii) Br, iv) OCH₂R₁, v) N(CH₃)₂, vi) NHSO₂CH₂R₁, vii) SCH₃ viii)NHCOCH₂R₁, or ix) NHSO₂C₆H₄X₁, wherein X₁ is a. H, b. CH₃, c. F, or d.CN; g) —CH═CH—C₆H₅, (cis or trans); h) —CH≡C—C₆H₅); i) CH═CH—C₆H₃X₂wherein X₂ is a. F, b. Cl, c. OCH₃, or d. —O—CH₂O;

wherein CH₂CH₂ is appended to the 1- or 2-positions; or

wherein i) —CH₂CH₂— appended to the 2- or 3-positions, ii) X₃ is a. O,b. S, c. NH, d. —NCH₃, and iii) R₇ is a. CH₃, or b. CH₃CH₂; wherein R₄is —H or —CH₃; and wherein R₅ is —H or —CH₃; provided that when R₁ is—CH₃ and R₂ is —H or —CH₃, R₄ is not —H.
 12. The composition of claim 11wherein the compound is selected from the group consisting of:2,3-Dimethyl-α-(2-phenylethynyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylmethyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(3-phenylpropyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-Di(2-phenylethyl)imidazo-[2,1-b]thiazole-5-methanol,α,3-Dimethyl-α-(E-2-phenyl-E-ethenyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(2-phenylpropyl)imidazo[2,1-b]thiazole-5-methanol,α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(4-bromophenylethyl)imidazo[2,1-b]thiazole-5-methanol,3-Methyl-α-(4-phenylbutyl)imidazo-[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol,2,3-Dimethyl-α-(2-phenylethenyl)imidazo[2,1-b]thiazole-5-methanol,6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol,5,6,7,8-Tetrahydro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,6,7,8,9-Tetrahydro-α-(2-phenylethyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol,6,7,8,9-Tetrahydro-α-(4-phenylbutyl)-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol,5,6,7,8,9,10-Hexahydro-α-(2-phenylethyl)cyclooct[d]imidazo-[2,1-b]thiazole-3-methanol,α-(2-phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol,7-Methyl-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,7-Fluoro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,7-Methoxy-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol,α-[2-(3-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-imidazo[2,1-b]thiazole-3-methanolα-[2-(3-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(4-Fluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,[α-[2-(4-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(3-Bromophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-2,1-b]thiazol-3-methanol,α-[2-(3-Chlorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(3,5-Difluorophenyl)ethyl]-16,7,8,9-tetrahydro-5H-cyclohept[d]-imidazothiazol-3-methanol,]α-[2-(4-dimethylaminophenyl)ethyl-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-[2,1-b]thiazol-3methanol,α-[2-(4-Dimethylaminophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-methanol,N-[3-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxypropyl]phenyl-4-methylbenzenesulfonamide,N-[2-[3-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-propyl]phenyl-4-methylbenzensulfonamide,[α-[2-(2,3-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo-thiazol-3-methanol,]α-[2-(4-methoxyphenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol,and[α[2-(4-methoxyphenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol,]α-[2-(2-Naphthalenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol],α-[2-(2-Furanyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethenyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol,and α-[2-(2-Furanyl)ethyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol].13. A compound selected from the group consisting of:α-[2-(4-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(3,5-Difluorophenyl)ethyl]-1-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazothiazol-3-methanol,α-[2-(2,3-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazothiazol-3-methanol,α-[2-(4-methoxyphenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethenyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol,and α-[2-(2-Furanyl)ethyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol.14. A method for treatment of mammals infected with a retrovirus, saidmethod comprising administering to a mammal infected with saidretrovirus a therapeutically effective amount of a compound selectedfrom the group consisting of:α-[2-(4-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(3,5-Difluorophenyl)ethyl]-1-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazothiazol-3-methanol,α-[2-(2,3-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazothiazol-3-methanol,α-[2-(4-methoxyphenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α-[2-(2-Furanyl)ethenyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol,and α-[2-(2-Furanyl)ethyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol.15. A pharmaceutical composition for use in treatment of a mammalinfected with a retrovirus, said composition comprising apharmaceutically acceptable solvent, diluent, adjuvant or carrier and,as the active ingredient, from about 0.1 mg to 100 mg per kg of bodyweight per day of a compound selected from the group consisting of:α[2-(4-Fluorophenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α[2-(3,5-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazothiazol-3-methanol,α[2-(2,3-Difluorophenyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]-imidazothiazol-3-methanol,α[2-(4-methoxyphenyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept-[d]imidazo[2,1-b]thiazol-3-methanol,α[2-(2-Furanyl)ethenyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α[2-(2-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α[2-(3-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol,α[2-(2-Furanyl)ethenyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol, andα[2-(2-Furanyl)ethyl]2,3-dimethylimidazo[2,1-b]thiazol-3-methanol.